Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors
Open accessAbstract
Cyclin-dependent kinases 12 and 13 (CDK12 and 13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and 13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and 13 covalent inhibitor, THZ531. Co-crystallization with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super–enhancer–associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and 13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
THZ531, a bulky covalent CDK12/13 inhibitor predicted to clash with DDB1, locks the CDK12 C-terminal extension in a conformation incompatible with DDB1 recruitment.
“THZ53124, a bulky covalent CDK12/13 inhibitor predicted to clash with DDB1 (Extended Data Fig. 6d–f), locks the CDK12 C-terminal extension in a conformation incompatible with DDB1 recruitment (Extended Data Fig. 6d).”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [24]
THZ531 lowered the TR-FRET signal and reduced in vitro cycK ubiquitination below DMSO control levels.
“Consistently, THZ531 further decreased the TR-FRET signal and diminished cycK ubiquitination in vitro below DMSO control levels (Fig. 3d, Extended Data Fig. 6c, f)24.”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [24]
The ‘THZ531 covalently inhibits CDK12 and 13’ section reports kinase inhibition, and the ‘In vitro kinase assays’ section describes phosphorylation measurements, but neither reports a TR-FRET signal or cyclin K ubiquitination. Searches for TR-FRET and cyclin K ubiquitination found no passage addressing the claimed reductions relative to DMSO. Page numbers were not available in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measuredTHZ531, a CDK12-CDK13 covalent inhibitor, binds with CDK12-cyclin K via a cysteine residue that is located outside the kinase domain.
“THZ531, a CDK12-CDK13 covalent inhibitor, binds with CDK12-cyclin K via a cysteine residue that is located outside the kinase domain [97].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [97]
THZ531 induced cell death and apoptosis in Ewing sarcoma cancer cell lines.
“Furthermore, THZ531 induced cell death and apoptosis in Ewing sarcoma cancer cell lines.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [97]
HQ461-mediated depletion of Cyclin K phenotypically mimics dual inhibition of CDK12 and CDK13 by the CDK12/13-selective inhibitor THZ531 to trigger cell death.
“Consistent with this notion, HQ461-mediated depletion of Cyclin K phenotypically mimics dual inhibition of CDK12 and CDK13 by the CDK12/13-selective inhibitor THZ531 to trigger cell death (Zhang et al., 2016).”
From Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation (2020) · cites this paper as Zhang et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 27,510 · see citing works
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386 · see citing works
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463 · see citing works
<i>MolProbity</i> : all-atom structure validation for macromolecular crystallography
Chen, V. B., Arendall, W. B., Headd, J. J., Keedy, D. A., Immormino, R. M., Kapral, G. J., Murray, L. W., Richardson, J. S., & Richardson, D. C. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909042073 · Cited by 14,115 · see citing works
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn923 · Cited by 14,108 · see citing works
Overview of the <i>CCP</i> 4 suite and current developments
Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G. W., McCoy, A., et al. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910045749 · Cited by 12,353 · see citing works
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197 · see citing works
REFMAC 5 for the refinement of macromolecular crystal structures
Murshudov, G. N., Skubák, P., Lebedev, A. A., Pannu, N. S., Steiner, R. A., Nicholls, R. A., Winn, M., Long, F., & Vagin, A. A. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444911001314 · Cited by 8,385 · see citing works
How good are my data and what is the resolution?
Evans, P. R., & Murshudov, G. N. (2013) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444913000061 · Cited by 4,747 · see citing works
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143 · see citing works
Self-citationSelective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.036 · Cited by 2,961 · see citing works
Self-citationTranscriptional Amplification in Tumor Cells with Elevated c-Myc
Lin, C. Y., Lovén, J., Rahl, P. B., Paranal, R. M., Burge, C. B., Bradner, J. E., Lee, T. I., & Young, R. A. (2012) · Cell · doi:10.1016/j.cell.2012.08.026 · Cited by 1,498 · see citing works
Self-citationControlling the elongation phase of transcription with P-TEFb
Peterlin, B. M., & Price, D. H. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.06.014 · Cited by 1,144 · see citing works
Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia
Ferrando, A. A., Neuberg, D. S., Staunton, J. E., Loh, M. L., Huard, C., Raimondi, S. C., Behm, F. G., Pui, C., Downing, J. R., Gilliland, D. G., et al. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00018-1 · Cited by 1,130 · see citing works
Rottenberg, S., Jaspers, J. E., Kersbergen, A. J., van der Burg, E., Nygren, A. O. H., Zander, S. A. L., Derksen, P. W. B., de Bruin, M., Zevenhoven, J., Lau, A., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806092105 · Cited by 954 · see citing works
RefSeq: an update on mammalian reference sequences
Pruitt, K. D., Brown, G., Hiatt, S. M., Thibaud‐Nissen, F., Astashyn, A., Ermolaeva, O. D., Farrell, C. M., Hart, J. A., Landrum, M., McGarvey, K. M., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1114 · Cited by 936 · see citing works
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor
Kwiatkowski, N. P., Zhang, T., Rahl, P. B., Abraham, B. J., Reddy, J., Ficarro, S. B., Dastur, A., Amzallag, A., Ramaswamy, S., Tesar, B. M., et al. (2014) · Nature · doi:10.1038/nature13393 · Cited by 865 · see citing works
Self-citationAn oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element
Mansour, M. R., Abraham, B. J., Anders, L., Berezovskaya, A., Gutierrez, A., Durbin, A. D., Etchin, J., Lawton, L., Sallan, S. E., Silverman, L. B., et al. (2014) · Science · doi:10.1126/science.1259037 · Cited by 801 · see citing works
Self-citationProgression through the RNA Polymerase II CTD Cycle
Buratowski, S. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.10.019 · Cited by 777 · see citing works
Young, R. A. (1991) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.60.070191.003353 · Cited by 729 · see citing works
Self-citationCDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer
Chipumuro, E., Marco, E., Christensen, C. L., Kwiatkowski, N. P., Zhang, T., Hatheway, C. M., Abraham, B. J., Sharma, B., Yeung, C. M., Altabef, A. B., et al. (2014) · Cell · doi:10.1016/j.cell.2014.10.024 · Cited by 631 · see citing works
Self-citationRevisiting Global Gene Expression Analysis
Lovén, J., Orlando, D. A., Sigova, A. A., Lin, C. Y., Rahl, P. B., Burge, C. B., Levens, D. L., Lee, T. I., & Young, R. A. (2012) · Cell · doi:10.1016/j.cell.2012.10.012 · Cited by 616 · see citing works
Self-citationDefining mechanisms that regulate RNA polymerase II transcription in vivo
Fuda, N. J., Ardehali, M. B., & Lis, J. T. (2009) · Nature · doi:10.1038/nature08449 · Cited by 576 · see citing works
Blazek, D., Kohoutek, J., Bartholomeeusen, K., Johansen, E., Hulinkova, P., Luo, Z., Cimermancic, P., Ule, J., & Peterlin, B. M. (2011) · Genes & Development · doi:10.1101/gad.16962311 · Cited by 522 · see citing works
Ahn, S., Kim, M., & Buratowski, S. (2004) · Molecular Cell · doi:10.1016/s1097-2765(03)00492-1 · Cited by 517 · see citing works
Zhang, Z., & Marshall, A. G. (1998) · Journal of the American Society for Mass Spectrometry · doi:10.1016/s1044-0305(97)00284-5 · Cited by 511 · see citing works
Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor
Christensen, C. L., Kwiatkowski, N. P., Abraham, B. J., Carretero, J., Al‐Shahrour, F., Zhang, T., Chipumuro, E., Herter-Sprie, G. S., Akbay, E. A., Altabef, A. B., et al. (2014) · Cancer Cell · doi:10.1016/j.ccell.2014.10.019 · Cited by 440 · see citing works
Self-citationCho, E., Kobor, M. S., Kim, M. K., Greenblatt, J., & Buratowski, S. (2001) · Genes & Development · doi:10.1101/gad.935901 · Cited by 428 · see citing works
CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1Preprint
Bartkowiak, B., Liu, P., Phatnani, H. P., Fuda, N. J., Cooper, J. J., Price, D. H., Adelman, K., Lis, J. T., & Greenleaf, A. L. (2010) · Genes & Development · doi:10.1101/gad.1968210 · Cited by 404 · see citing works
Self-citationCyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II
Larochelle, S., Amat, R., Glover-Cutter, K. M., Sansó, M., Zhang, C., Allen, J. J., Shokat, K. M., Bentley, D. L., & Fisher, R. P. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2399 · Cited by 394 · see citing works
Bajrami, I., Frankum, J. R., Konde, A., Miller, R. E., Rehman, F. L., Brough, R., Campbell, J., Sims, D., Rafiq, R., Hooper, S., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2541 · Cited by 373 · see citing works
In Situ Kinase Profiling Reveals Functionally Relevant Properties of Native Kinases
Patricelli, M. P., Nomanbhoy, T. K., Wu, J., Brown, H., Zhou, D., Zhang, J., Jagannathan, S., Aban, A., Okerberg, E. S., Herring, C., et al. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.04.011 · Cited by 357 · see citing works
Self-citationDiscovery of Potent and Selective Covalent Inhibitors of JNK
Zhang, T., Iñesta-Vaquera, F., Niepel, M., Zhang, J., Ficarro, S. B., Machleidt, T., Xie, T., Marto, J. A., Kim, N., Sim, T., et al. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.11.010 · Cited by 348 · see citing works
Self-citationSite‐specific recombination of the tal‐1 gene is a common occurrence in human T cell leukemia.
Brown, J. L., Cheng, J. T., Chen, Q., Siciliano, M. J., Crist, W., Buchanan, G., & Baer, R. J. (1990) · The EMBO Journal · doi:10.1002/j.1460-2075.1990.tb07535.x · Cited by 339 · see citing works
Sanda, T., Lawton, L. N., Barrasa, M. I., Fan, Z. P., Kohlhammer, H., Gutiérrez, A., Ma, W., Tatarek, J., Ahn, Y., Kelliher, M. A., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.06.007 · Cited by 333 · see citing works
Self-citationThe multi-tasking P-TEFb complex
Brès, V., Yoh, S. M., & Jones, K. A. (2008) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2008.04.008 · Cited by 230 · see citing works
Joshi, P. M., Sutor, S. L., Huntoon, C. J., & Karnitz, L. M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.551143 · Cited by 201 · see citing works
Liang, K., Gao, X., Gilmore, J. M., Florens, L. A., Washburn, M. P., Smith, E. R., & Shilatifard, A. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.01426-14 · Cited by 194 · see citing works
Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition
Czudnochowski, N., Bösken, C. A., & Geyer, M. (2012) · Nature Communications · doi:10.1038/ncomms1846 · Cited by 191 · see citing works
Self-citationThe structure and substrate specificity of human Cdk12/Cyclin K
Bösken, C. A., Farnung, L., Hintermair, C., Merzel Schachter, M., Vogel-Bachmayr, K., Blazek, D., Anand, K., Fisher, R. P., Eick, D., & Geyer, M. (2014) · Nature Communications · doi:10.1038/ncomms4505 · Cited by 191 · see citing works
Self-citationDavidson, L., Muniz, L., & West, S. (2014) · Genes & Development · doi:10.1101/gad.231274.113 · Cited by 171 · see citing works
Structural and functional analysis of the Cdk13/Cyclin K complex
Greifenberg, A. K., Hönig, D., Pilarova, K., Düster, R., Bartholomeeusen, K., Bösken, C. A., Anand, K., Blazek, D., & Geyer, M. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.025 · Cited by 157 · see citing works
Self-citationEkumi, K. M., Paculová, H., Lenasi, T., Pospíchalová, V., Bösken, C. A., Rybaříková, J., Bryja, V., Geyer, M., Blažek, D., & Barborič, M. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv101 · Cited by 145 · see citing works
Self-citationChen, H.-H., Wang, Y.-C., & Fann, M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.7.2736-2745.2006 · Cited by 144 · see citing works
The carboxy terminal domain of RNA polymerase II and alternative splicing
Muñoz, M. J., de la Mata, M., & Kornblihtt, A. R. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.03.010 · Cited by 143 · see citing works
The Crystal Structure of Human CDK7 and Its Protein Recognition Properties
Lolli, G., Lowe, E. D., Brown, N. R., & Johnson, L. N. (2004) · Structure · doi:10.1016/j.str.2004.08.013 · Cited by 141 · see citing works
Cheng, S.-W. G., Kuzyk, M. A., Moradian, A., Ichu, T.-A., Chang, V. C.-D., Tien, J. F., Vollett, S. E., Griffith, M., Marra, M. A., & Morin, G. B. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06267-11 · Cited by 124 · see citing works
Ficarro, S. B., Zhang, Y., Lu, Y., Moghimi, A. R., Askenazi, M., Hyatt, E., Smith, E. D., Boyer, L. F., Schlaeger, T. M., Luckey, C. J., et al. (2009) · Analytical Chemistry · doi:10.1021/ac802720e · Cited by 110 · see citing works
Self-citationRNA Polymerase II transcription elongation and Pol II CTD Ser2 phosphorylation
Bowman, E. A., & Kelly, W. G. (2014) · Nucleus · doi:10.4161/nucl.29347 · Cited by 108 · see citing works
CDK13/CDC2L5 interacts with L-type cyclins and regulates alternative splicing
Chen, H.-H., Wong, Y., Genevière, A., & Fann, M. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.01.049 · Cited by 83 · see citing works
Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts
Eifler, T., Shao, W., Bartholomeeusen, K., Fujinaga, K., Jäger, S., Johnson, J. R., Luo, Z., Krogan, N. J., & Peterlin, B. M. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01157-14 · Cited by 63 · see citing works
Sansó, M., & Fisher, R. P. (2013) · Transcription · doi:10.4161/trns.25146 · Cited by 62 · see citing works
mzAPI: a new strategy for efficiently sharing mass spectrometry data
Askenazi, M., Parikh, J. R., & Marto, J. A. (2009) · Nature Methods · doi:10.1038/nmeth0409-240 · Cited by 62 · see citing works
Self-citationBartkowiak, B., & Greenleaf, A. L. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.612226 · Cited by 54 · see citing works
Self-citationEngineering an analog-sensitive CDK12 cell line using CRISPR/Cas
Bartkowiak, B., Yan, C. M., & Greenleaf, A. L. (2015) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2015.07.010 · Cited by 46 · see citing works
Self-citationYeast Screens Identify the RNA Polymerase II CTD and SPT5 as Relevant Targets of BRCA1 Interaction
Bennett, C. B., Westmoreland, T. J., Verrier, C. S., Blanchette, C., Winsor, T. S., Phatnani, H. P., Mishina, Y. V., Hüper, G., Selim, A. L., Madison, E. R., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001448 · Cited by 31 · see citing works
Self-citationA DNA Damage Response System Associated with the phosphoCTD of Elongating RNA Polymerase II
Winsor, T. S., Bartkowiak, B., Bennett, C. B., & Greenleaf, A. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060909 · Cited by 23 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 8
- [39]39. Kwiatkowski N, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014; 511:616-620. [PubMed: 25043025]
- [40]40. Bosken CA, et al. The structure and substrate specificity of human Cdk12/Cyclin K. Nature communications. 2014; 5:3505.
- [46]46. Kabsch W. Xds. Acta crystallographica. Section D, Biological crystallography. 2010; 66:125-132. [PubMed: 20124692]
- [48]48. Winn MD, et al. Overview of the CCP4 suite and current developments. Acta crystallographica. Section D, Biological crystallography. 2011; 67:235-242. [PubMed: 21460441]
- [49]49. McCoy AJ, et al. Phaser crystallographic software. J Appl Crystallogr. 2007; 40:658-674. [PubMed: 19461840]
- [51]51. Murshudov GN, et al. REFMAC5 for the refinement of macromolecular crystal structures. Acta crystallographica. Section D, Biological crystallography. 2011; 67:355-367. [PubMed: 21460454]
- [57]57. Bartkowiak B, Greenleaf AL. Expression, purification, and identification of associated proteins of the full-length hCDK12/CyclinK complex. The Journal of biological chemistry. 2015; 290:1786- 1795. [PubMed: 25429106]
- [63]63. Mansour MR, et al. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science. 2014; 346:1373-1377. [PubMed: 25394790]
Cited by
Sorted by citations
Transcriptional Addiction in Cancer
Bradner, J. E., Hnisz, D., & Young, R. A. (2017) · Cell · doi:10.1016/j.cell.2016.12.013 · Cited by 1,188 · see citing works
Self-citationKinase inhibitors: the road ahead
Ferguson, F. M., & Gray, N. S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.21 · Cited by 1,009 · see citing works
Self-citationPharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation
Olson, C. M., Jiang, B., Erb, M. A., Liang, Y., Doctor, Z. M., Zhang, Z., Zhang, T., Kwiatkowski, N., Boukhali, M., Green, J. L., et al. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2538 · Cited by 552 · see citing works
Self-citationThe CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K
Słabicki, M., Kozicka, Z., Petzold, G., Li, Y.-D., Manojkumar, M., Bunker, R. D., Donovan, K. A., Sievers, Q. L., Koeppel, J., Suchyta, D., et al. (2020) · Nature · doi:10.1038/s41586-020-2374-x · Cited by 433 · see citing works
Inhibitors of cyclin-dependent kinases as cancer therapeutics.
Whittaker, S. R., Mallinger, A., Workman, P., & Clarke, P. A. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.008 · Cited by 384 · see citing works
Rational discovery of molecular glue degraders via scalable chemical profiling
Mayor-Ruiz, C., Bauer, S., Brand, M., Kozicka, Z., Siklos, M., Imrichova, H., Kaltheuner, I. H., Hahn, E., Seiler, K., Koren, A., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0594-x · Cited by 369 · see citing works
Self-citationSuper-Enhancer-Driven Transcriptional Dependencies in Cancer
Sengupta, S., & George, R. E. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.03.006 · Cited by 349 · see citing works
Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer
Quereda, V., Bayle, S., Vena, F., Frydman, S. M., Monastyrskyi, A., Roush, W. R., & Duckett, D. R. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.09.004 · Cited by 352 · see citing works
Advances in covalent kinase inhibitors
Abdeldayem, A., Raouf, Y. S., Constantinescu, S. N., Moriggl, R., & Gunning, P. T. (2020) · Chemical Society Reviews · doi:10.1039/c9cs00720b · Cited by 332 · see citing works
CDK12 regulates DNA repair genes by suppressing intronic polyadenylation
Dubbury, S. J., Boutz, P. L., & Sharp, P. A. (2018) · Nature · doi:10.1038/s41586-018-0758-y · Cited by 318 · see citing works
Transcription-Associated Cyclin-Dependent Kinases as Targets and Biomarkers for Cancer Therapy
Chou, J., Quigley, D. A., Robinson, T. M., Feng, F. Y.-C., & Ashworth, A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0528 · Cited by 292 · see citing works
PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)
He, M., Cao, C., Ni, Z., Liu, Y., Song, P., Hao, S., He, Y., Sun, X., & Rao, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00999-9 · Cited by 283 · see citing works
CDK inhibitors in cancer therapy, an overview of recent development.
Zhang, M., Zhang, L., Hei, R., Li, X., Cai, H., Wu, X., Zheng, Q., & Cai, C. (2021) · PubMed Central · Cited by 282 · see citing works
Krajewska, M., Dries, R., Grassetti, A. V., Dust, S., Gao, Y., Huang, H., Sharma, B., Day, D. S., Kwiatkowski, N., Pomaville, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09703-y · Cited by 281 · see citing works
Self-citationCovalent Inhibition in Drug Discovery
Ghosh, A. K., Samanta, I., Mondal, A., & Liu, W. R. (2019) · ChemMedChem · doi:10.1002/cmdc.201900107 · Cited by 265 · see citing works
The Cysteinome of Protein Kinases as a Target in Drug Development
Chaikuad, A., Koch, P., Laufer, S., & Knapp, S. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201707875 · Cited by 237 · see citing works
Zhang, H., Christensen, C. L., Dries, R., Oser, M. G., Deng, J., Diskin, B., Li, F., Pan, Y., Zhang, X., Yin, Y., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.11.003 · Cited by 218 · see citing works
Self-citationDiscovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation
Lv, L., Chen, P., Cao, L., Li, Y., Zeng, Z., Cui, Y., Wu, Q., Li, J., Wang, J.-H., Dong, M.-Q., et al. (2020) · eLife · doi:10.7554/elife.59994 · Cited by 215 · see citing works
CDK7 inhibitors as anticancer drugs
Sava, G. P., Fan, H., Coombes, R. C., Buluwela, L., & Ali, S. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09885-8 · Cited by 204 · see citing works
Progress with covalent small-molecule kinase inhibitors
Zhao, Z., & Bourne, P. E. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.01.035 · Cited by 200 · see citing works
Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015–2019)
Sánchez-Martínez, C., Lallena, M. J., Sanfeliciano, S. G., & de Dios, A. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126637 · Cited by 200 · see citing works
Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation
Zhang, T., Hatcher, J. M., Teng, M., Gray, N. S., & Kostic, M. (2019) · Cell Chemical Biology · doi:10.1016/j.chembiol.2019.09.012 · Cited by 178 · see citing works
Self-citationEWS/FLI confers tumor cell synthetic lethality to CDK12 inhibition in Ewing sarcoma
Iniguez, A. B., Stolte, B., Wang, E. J., Conway, A. S., Alexe, G., Dharia, N. V., Kwiatkowski, N., Zhang, T., Abraham, B. J., Mora, J., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2017.12.009 · Cited by 173 · see citing works
Self-citationCDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion
Tien, J. F., Mazloomian, A., Cheng, S., Hughes, C. S., Chow, C. C. T., Canapi, L. T., Oloumi, A., Trigo‐Gonzalez, G., Bashashati, A., Xu, J., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx187 · Cited by 165 · see citing works
Targeting transcription cycles in cancer
Vervoort, S., Devlin, J., Kwiatkowski, N., Teng, M.-X., Gray, N., & Johnstone, R. (2021) · Nature Reviews. Cancer · doi:10.1038/s41568-021-00411-8 · Cited by 140 · see citing works
Self-citationDevelopment of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype
Olson, C. M., Liang, Y., Leggett, A. L., Park, W. D., Li, L., Mills, C. E., Elsarrag, S. Z., Ficarro, S. B., Zhang, T., Düster, R., et al. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.02.012 · Cited by 165 · see citing works
Self-citationCDK13 cooperates with CDK12 to control global RNA polymerase II processivity
Fan, Z., Devlin, J. R., Hogg, S. J., Doyle, M. A., Harrison, P. F., Todorovski, I., Cluse, L. A., Knight, D. A., Sandow, J. J., Gregory, G., et al. (2020) · Science Advances · doi:10.1126/sciadv.aaz5041 · Cited by 164 · see citing works
Self-citationSmall-molecule targeting of brachyury transcription factor addiction in chordoma
Sharifnia, T., Wawer, M. J., Chen, T., Huang, Q., Weir, B. A., Sizemore, A. E., Lawlor, M. A., Goodale, A. B., Cowley, G. S., Vázquez, F., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0312-3 · Cited by 164 · see citing works
Self-citationCDK9 inhibitors in acute myeloid leukemia
Boffo, S., Damato, A., Alfano, L., & Giordano, A. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0704-8 · Cited by 158 · see citing works
Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13
Zeng, M., Kwiatkowski, N. P., Zhang, T., Nabet, B., Xu, M., Liang, Y., Quan, C., Wang, J., Hao, M., Palakurthi, S. S., et al. (2018) · eLife · doi:10.7554/elife.39030 · Cited by 152 · see citing works
Self-citationDiscovery and resistance mechanism of a selective CDK12 degrader
Jiang, B., Gao, Y., Che, J., Lu, W., Kaltheuner, I. H., Dries, R., Kalocsay, M., Berberich, M. J., Jiang, J., You, I., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00765-y · Cited by 150 · see citing works
Self-citationDiscovery of Cysteine-targeting Covalent Protein Kinase Inhibitors
Lu, X., Smaill, J. B., Patterson, A. V., & Ding, K. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01719 · Cited by 146 · see citing works
Cdk7: a kinase at the core of transcription and in the crosshairs of cancer drug discovery
Fisher, R. P. (2018) · Transcription · doi:10.1080/21541264.2018.1553483 · Cited by 145 · see citing works
A proteome-wide atlas of drug mechanism of action
Mitchell, D. C., Kuljanin, M., Li, J., Vranken, J. G. V., Bulloch, N. J., Schweppe, D. K., Huttlin, E. L., & Gygi, S. P. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01539-0 · Cited by 142 · see citing works
Covalent inhibitors: an opportunity for rational target selectivity
Lagoutte, R., Patouret, R., & Winssinger, N. (2017) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2017.05.008 · Cited by 138 · see citing works
Selective and reversible modification of kinase cysteines with chlorofluoroacetamides
Shindo, N., Fuchida, H., Sato, M., Watari, K., Shibata, T., Kuwata, K., Miura, C., Okamoto, K., Hatsuyama, Y., Tokunaga, K., et al. (2019) · Nature Chemical Biology · doi:10.1038/s41589-018-0204-3 · Cited by 137 · see citing works
Fragment-based covalent ligand discovery
Lu, W., Kostic, M., Zhang, T., Che, J., Patricelli, M. P., Jones, L. H., Chouchani, E. T., & Gray, N. S. (2021) · RSC Chemical Biology · doi:10.1039/d0cb00222d · Cited by 136 · see citing works
Self-citationCDK12: an emerging therapeutic target for cancer
Lui, G. Y. L., Grandori, C., & Kemp, C. J. (2018) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2018-205356 · Cited by 136 · see citing works
Lysine-Targeted Inhibitors and Chemoproteomic Probes
Cuesta, A., & Taunton, J. (2019) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044805 · Cited by 135 · see citing works
Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
Rusan, M., Li, K., Li, Y. Y., Christensen, C. L., Abraham, B. J., Kwiatkowski, N. P., Buczkowski, K. A., Bockorny, B., Chen, T., Li, S., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0461 · Cited by 128 · see citing works
Self-citationDetermining Cysteines Available for Covalent Inhibition Across the Human Kinome
Zhao, Z., Liu, Q., Bliven, S. E., Xie, L., & Bourne, P. E. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01815 · Cited by 126 · see citing works
A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response
Hoshii, T., Cifani, P., Feng, Z., Huang, C., Koche, R. P., Chen, C.-W. D., Delaney, C. D., Lowe, S. W., Kentsis, A., & Armstrong, S. A. (2018) · Cell · doi:10.1016/j.cell.2018.01.032 · Cited by 120 · see citing works
CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1‐ErbB‐PI3K signaling
Choi, H., Jin, S., Cho, H., Won, H., An, H. W., Jeong, G., Park, Y., Kim, H.-Y., Park, M. K., Son, T., et al. (2019) · EMBO Reports · doi:10.15252/embr.201948058 · Cited by 119 · see citing works
CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes
Manavalan, A. P. C., Pilařová, K., Kluge, M., Bartholomeeusen, K., Rájecký, M., Oppelt, J., Khirsariya, P., Paruch, K., Krejčí, L., Friedel, C. C., et al. (2019) · EMBO Reports · doi:10.15252/embr.201847592 · Cited by 110 · see citing works
Recent development of CDK inhibitors: An overview of CDK/inhibitor co-crystal structures
Cheng, W., Yang, Z., Wang, S., Li, Y., Han, W., Tian, X., & Kan, Q. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.01.003 · Cited by 111 · see citing works
Spatially clustered loci with multiple enhancers are frequent targets of HIV-1 integration
Lucic, B., Chen, H., Kuzman, M., Zorita, E. V., Wegner, J., Minneker, V., Wang, W., Fronza, R., Laufs, S., Schmidt, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12046-3 · Cited by 106 · see citing works
Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes
Hartung, I. V., Rudolph, J., Mader, M. M., Mulder, M. P. C., & Workman, P. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00550 · Cited by 109 · see citing works
Wang, C., Wang, H., Lieftink, C., du Chatinier, A., Gao, D., Jin, G., Jin, H., Beijersbergen, R. L., Qin, W., & Bernards, R. (2020) · Gut · doi:10.1136/gutjnl-2019-318506 · Cited by 107 · see citing works
Terai, H., Kitajima, S., Potter, D. S., Matsui, Y., Quiceno, L. G., Chen, T., Kim, T. J., Rusan, M., Thai, T. C., Piccioni, F., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1904 · Cited by 105 · see citing works
Self-citationHuman CDK12 and CDK13, multi-tasking CTD kinases for the new millenium
Greenleaf, A. L. (2018) · Transcription · doi:10.1080/21541264.2018.1535211 · Cited by 105 · see citing works
Self-citationTherapeutic targeting of transcriptional cyclin-dependent kinases
Galbraith, M. D., Bender, H., & Espinosa, J. M. (2018) · Transcription · doi:10.1080/21541264.2018.1539615 · Cited by 105 · see citing works
Cayrol, F., Praditsuktavorn, P., Fernando, T. M., Kwiatkowski, N. P., Marullo, R., Calvo-Vidal, M. N., Phillip, J. M., Pera, B., Yang, S. N., Takpradit, K., et al. (2017) · Nature Communications · doi:10.1038/ncomms14290 · Cited by 103 · see citing works
Self-citationDissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors
Parua, P. K., & Fisher, R. P. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0563-4 · Cited by 104 · see citing works
Tellier, M., Zaborowska, J., Caizzi, L., Mohammad, E., Velychko, T., Schwalb, B., Vicens, I. F., Blears, D., Nojima, T., Cramer, P., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa514 · Cited by 101 · see citing works
Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action
Łukasik, P., Baranowska‐Bosiacka, I., Kulczycka, K., & Gutowska, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062806 · Cited by 101 · see citing works
Clarke, P. A., Ortiz-Ruiz, M.-J., Poele, R. T., Adeniji-Popoola, O., Box, G., Court, W., Czasch, S., Bawab, S. E., Esdar, C., Ewan, K., et al. (2016) · eLife · doi:10.7554/elife.20722 · Cited by 99 · see citing works
CDK9 keeps RNA polymerase II on track
Egloff, S. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03878-8 · Cited by 99 · see citing works
The design and development of covalent protein-protein interaction inhibitors for cancer treatment
Cheng, S.-S., Yang, G.-J., Wang, W., Leung, C.-H., & Ma, D.-L. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00850-0 · Cited by 98 · see citing works
Foulkes, D. M., Byrne, D. P., Yeung, W., Shrestha, S., Bailey, F. P., Ferries, S., Eyers, C. E., Keeshan, K., Wells, C. I., Drewry, D. H., et al. (2018) · Science Signaling · doi:10.1126/scisignal.aat7951 · Cited by 94 · see citing works
Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13
Yang, J., Chang, Y., Tien, J. C.-Y., Wang, Z., Zhou, Y., Zhang, P., Huang, W., Vo, J. N., Apel, I. J., Wang, C., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00384 · Cited by 96 · see citing works
Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer
Dieter, S. M., Siegl, C., Codó, P. L., Huerta, M., Ostermann-Parucha, A. L., Schulz, E., Zowada, M. K., Martin, S., Laaber, K., Nowrouzi, A., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109394 · Cited by 95 · see citing works
Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors
Kalra, S., Joshi, G., Munshi, A., & Kumar, R. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.08.071 · Cited by 92 · see citing works
A Chemoproteomic Strategy for Direct and Proteome-Wide Covalent Inhibitor Target-Site Identification
Browne, C. M., Jiang, B., Ficarro, S. B., Doctor, Z. M., Johnson, J. L., Card, J. D., Sivakumaren, S. C., Alexander, W. M., Yaron, T. M., Murphy, C. J., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b07911 · Cited by 90 · see citing works
Self-citationNiu, T., Li, K., Li, J., Zhou, Z., Hong, J.-E., Chen, X., Dong, X., He, Q., Cao, J., Yang, B., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.114012 · Cited by 90 · see citing works
Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors
Richters, A., Doyle, S. K., Freeman, D. B., Lee, C., Leifer, B. S., Jagannathan, S., Kabinger, F., Koren, J. V., Struntz, N. B., Urgiles, J., et al. (2021) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.10.001 · Cited by 86 · see citing works
Self-citationThe emerging roles of CDK12 in tumorigenesis
Paculová, H., & Kohoutek, J. (2017) · Cell Division · doi:10.1186/s13008-017-0033-x · Cited by 79 · see citing works
Predicting master transcription factors from pan-cancer expression data
Reddy, J., Fonseca, M. A., Corona, R. I., Nameki, R. A., Dezem, F. S., Klein, I. A., Chang, H. S. Y., Chaves‐Moreira, D., Afeyan, L. K., Malta, T. M., et al. (2021) · Science Advances · doi:10.1126/sciadv.abf6123 · Cited by 77 · see citing works
Self-citationTranscriptional elongation control in developmental gene expression, aging, and disease
Aoi, Y., & Shilatifard, A. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.10.004 · Cited by 83 · see citing works
CDK7 Inhibitors in Cancer Therapy: The Sweet Smell of Success?
Diab, S., Yu, M., & Wang, S. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01985 · Cited by 81 · see citing works
Chromatin dependencies in cancer and inflammation
Marazzi, I., Greenbaum, B. D., Low, D. H. P., & Guccione, E. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.113 · Cited by 80 · see citing works
Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors
Gao, Y., Zhang, T., Terai, H., Ficarro, S. B., Kwiatkowski, N. P., Hao, M.-F., Sharma, B., Christensen, C. L., Chipumuro, E., Wong, K., et al. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.11.007 · Cited by 80 · see citing works
Self-citationTargeting DNA Damage Response in Prostate and Breast Cancer
Wengner, A. M., Scholz, A., & Haendler, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218273 · Cited by 78 · see citing works
CDK12: A Potent Target and Biomarker for Human Cancer Therapy
Liang, S., Hu, L., Wu, Z., Chen, Z., Liu, S., Xu, X., & Qian, A. (2020) · Cells · doi:10.3390/cells9061483 · Cited by 75 · see citing works
Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation
Lei, T., Zhang, P., Zhang, X., Xiao, X., Zhang, J., Qiu, T., Dai, Q., Zhang, Y., Min, L., Li, Q., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04258-w · Cited by 75 · see citing works
Chen, P., Sun, J., Zhu, C., Tang, G., Wang, W., Xu, M., Xiang, M., Zhang, C., Zhang, Z., Gao, L., et al. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202203878 · Cited by 75 · see citing works
Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors
Kalan, S., Amat, R., Schachter, M. M., Kwiatkowski, N. P., Abraham, B. J., Liang, Y., Zhang, T., Olson, C. M., Larochelle, S., Young, R. A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.056 · Cited by 74 · see citing works
Self-citationIto, M., Tanaka, T., Toita, A., Uchiyama, N., Kokubo, H., Morishita, N., Klein, M. G., Zou, H., Murakami, M., Kondo, M., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00683 · Cited by 73 · see citing works
Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery Efforts
Xie, Z., Hou, S., Yang, X., Duan, Y., Han, J., Wang, Q., & Liao, C. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c02190 · Cited by 73 · see citing works
The cryoelectron microscopy structure of the human CDK-activating kinase
Greber, B. J., Perez-Bertoldi, J. M., Lim, K., Iavarone, A. T., Toso, D. B., & Nogales, E. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2009627117 · Cited by 72 · see citing works
The Renaissance of Cyclin Dependent Kinase Inhibitors
Ettl, T., Schulz, D., & Bauer, R. J. (2022) · Cancers · doi:10.3390/cancers14020293 · Cited by 71 · see citing works
Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90
Cuesta, A., Wan, X., Burlingame, A. L., & Taunton, J. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.9b09684 · Cited by 69 · see citing works
Shi, Z., Tian, L., Qiang, T., Li, J., Xing, Y. Q., Ren, X., Liu, C., & Liang, C. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c02064 · Cited by 68 · see citing works
Covalent Aurora A regulation by the metabolic integrator coenzyme A
Tsuchiya, Y., Byrne, D. P., Burgess, S. G., Bormann, J., Baković, J., Huang, Y., Zhyvoloup, A., Yu, B. Y. K., Peak‐Chew, S., Tran, T. X. M., et al. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101318 · Cited by 68 · see citing works
Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome
Rao, S., Gurbani, D., Du, G., Everley, R. A., Browne, C. M., Chaikuad, A., Tan, L., Schröder, M., Gondi, S. R., Ficarro, S. B., et al. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.02.021 · Cited by 67 · see citing works
Self-citationCovalent Proximity Scanning of a Distal Cysteine to Target PI3Kα
Borsari, C., Keleş, E., McPhail, J. A., Schäfer, A., Sriramaratnam, R., Goch, W., Schaefer, T., Pascale, M. D., Bal, W., Gstaiger, M., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.1c13568 · Cited by 64 · see citing works
The era of high-quality chemical probes
Licciardello, M. P., & Workman, P. (2022) · RSC Medicinal Chemistry · doi:10.1039/d2md00291d · Cited by 60 · see citing works
Jiang, B., Jiang, J., Kaltheuner, I. H., Iniguez, A. B., Anand, K., Ferguson, F. M., Ficarro, S. B., Seong, B. K. A., Greifenberg, A. K., Dust, S., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113481 · Cited by 63 · see citing works
Self-citationQi, J., Yang, Z., Lin, T., Ma, L., Wang, Y., Zhang, Y., Gao, C.-C., Liu, K.-L., Li, W., Zhao, A., et al. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01814-5 · Cited by 61 · see citing works
Fast-acting chemical tools to delineate causality in transcriptional control
Jaeger, M. G., & Winter, G. E. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.02.015 · Cited by 60 · see citing works
Wu, H., Yao, H., He, C., Jia, Y., Zhu, Z., Xu, S., Li, D., & Xu, J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.03.019 · Cited by 60 · see citing works
Structure‐Based Design of Selective Noncovalent CDK12 Inhibitors
Johannes, J. W., Denz, C. R., Su, N., Wu, A. J., Impastato, A. C., Mlynarski, S. N., Varnes, J. G., Prince, D. B., Cidado, J. R., Gao, N., et al. (2017) · ChemMedChem · doi:10.1002/cmdc.201700695 · Cited by 60 · see citing works
The Promise and Current Status of CDK12/13 Inhibition for the Treatment of Cancer
Tadesse, S., Duckett, D. R., & Monastyrskyi, A. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0240 · Cited by 59 · see citing works
CDK regulators—Cell cycle progression or apoptosis—Scenarios in normal cells and cancerous cells
Nilmani, D'costa, M., Bothe, A., Das, S., Kumar, S. U., Ramanathan, G., & Doss, C. G. P. (2023) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2022.11.008 · Cited by 59 · see citing works
Synthetic Lethality through the Lens of Medicinal Chemistry
Myers, S. H., Ortega, J. A., & Cavalli, A. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00766 · Cited by 60 · see citing works
Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors
Sivakumaren, S. C., Shim, H., Zhang, T., Ferguson, F. M., Lundquist, M. R., Browne, C. M., Seo, H., Paddock, M. N., Manz, T. D., Jiang, B., et al. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.02.003 · Cited by 56 · see citing works
Self-citationRamírez-Moya, J., Miliotis, C., Baker, A. R., Gregory, R. I., Slack, F. J., & Santisteban, P. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01401-y · Cited by 56 · see citing works
Liu, Y., Hao, M., Leggett, A. L., Gao, Y., Ficarro, S. B., Che, J., He, Z., Olson, C. M., Marto, J. A., Kwiatkowski, N. P., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01929 · Cited by 55 · see citing works
Self-citationPhosphoproteome profiling uncovers a key role for CDKs in TNF signaling
Tanzer, M. C., Bludau, I., Stafford, C. A., Hornung, V., & Mann, M. (2021) · Nature Communications · doi:10.1038/s41467-021-26289-6 · Cited by 54 · see citing works
Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer
Cheng, L., Zhou, S., Zhou, S., Shi, K., Cheng, Y., Cai, M., Ye, K., Lin, L., Zhang, Z., Jia, C., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-0222 · Cited by 54 · see citing works
Brägelmann, J., Dammert, M. A., Dietlein, F., Heuckmann, J. M., Choidas, A., Böhm, S., Richters, A., Basu, D., Tischler, V., Lorenz, C., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.082 · Cited by 54 · see citing works
- Authors
- Zhang, T., Kwiatkowski, N., Olson, C. M., Dixon-Clarke, S. E., Abraham, B. J., Greifenberg, A. K., Ficarro, S. B., Elkins, J. M., Liang, Y., Hannett, N. M., Manz, T., Hao, M., Bartkowiak, B., Greenleaf, A. L., Marto, J. A., Geyer, M., Bullock, A. N., Young, R. A., & Gray, N. S.
- Affiliations
- Harvard University (US)
- University of Oxford (GB)
- Whitehead Institute for Biomedical Research (US)
- University of Bonn (DE)
- Dana-Farber Cancer Institute (US)
- Duke Medical Center (US)
- Corresponding author
- Young, Richard A
- Gray, Nathanael S
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2016-08-29
- Volume
- 12
- Issue
- 10
- Pages
- 876-884
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5033074
- OpenAlex
- W2512442926
- Semantic Scholar
- c8164ef9df7e4d3d418a7b07384190780d6ae6a3
- Cited by
- 374
- References
- 59
- Citations by year
- 2026: 39 · 2025: 35 · 2024: 50 · 2023: 44 · 2022: 40 · 2021: 49 · 2020: 38 · 2019: 27 · 2018: 21 · 2017: 27 · 2016: 4
- FWCI
- 13.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- PMC
- Funders
- Eli Lilly and Company
- Pfizer
- GlaxoSmithKline
- Dana-Farber/Harvard Cancer Center
- Genome Canada (OGI-055)
- Wellcome Trust (106169/Z/14/Z, 092809, 106169, 092809/Z/10/Z, 1097737)
- Diamond Light Source (mx8421, 1097737)
- Ontario Genomics
- Hope Funds for Cancer Research
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Ontario Genomics Institute (OGI-055, 092809/Z/10/Z)
- Ontario Ministry of Economic Development and Innovation (092809/Z/10/Z)
- Deutsche Forschungsgemeinschaft (GE 976/9-1)
- Ministero dello Sviluppo Economico
- National Institutes of Health (CA109901, CA179483)
- Medical Research Council
- National Human Genome Research Institute (R01HG002668)
- National Cancer Institute (R01CA179483, P01CA109901, P30CA014051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- CDK12, CDK13, covalent inhibitors, cyclin K, RNA polymerase II processivity, super-enhancers, DNA damage response genes, transcription factor expression, apoptosis, kinase inhibitors
- MeSH terms
- Anilides, Cysteine, DNA Damage, Humans, Pyrimidines, CDC2 Protein Kinase, Cell Death, Cyclin-Dependent Kinases, Protein Kinase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
