Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation
Open accessAbstract
Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.
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Several mechanisms contribute to increased selectivity of PROTACs, including steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.
“Several mechanisms have been shown to contribute to this increase in selectivity. This includes steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.62−69”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [64]
Degradation target profiles often differ vastly from parental inhibitor selectivity profiles because of a non-linear dependence on binding.
“Similarly, because of a non-linear dependence on binding, degradation target profiles often differ vastly from parental inhibitor selectivity profiles (Olson et al., 2018)”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Olson et al., 2018
It is widely believed that degraders uncouple efficacy from target occupancy.
“It is widely believed that degraders uncouple efficacy from target occupancy (Gadd et al., 2017; Nowak et al., 2018; Olson et al., 2018; Roy et al., 2019).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Olson et al., 2018
CRBNN351D led to a marked sensitization (15-fold shift in EC50) to THAL-SNS-032.
“Simultaneously, it led to a marked sensitization (15-fold shift in EC50) to the CDK9-targeting PROTAC THAL-SNS-03240 (Extended Data Fig. 6B and C).”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [40]
Selective degradation of CDK9 was achieved by converting the non-selective CDK inhibitor SNS-032 into a degrader.
“For example, selective degradation of CDK9 was achieved by converting the non-selective CDK inhibitor SNS-032 into a degrader[9].”
From Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 (2019) · cites this paper as [9]
PROTAC selectivity does not necessarily mimic that of its target-binding warhead, but rather depends sensitively on the linker.
“It has further been shown that PROTAC selectivity does not necessarily mimic that of its target-binding warhead, but rather depends sensitively on the linker 20, 23, 24, 33”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [24]
PROTACs can have a duration of action that extends beyond clearance and depends on the turnover rate of the protein target rather than residence time.
“and can have a duration of action that extends beyond clearance and depends on the turnover rate of the protein target rather than residence time 23,24,25 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [23]
Saturating doses of free PROTAC molecules can antagonize the binding of binary PROTAC-protein complexes to their ternary partner and abrogate catalytic degradation, a phenomenon known as the hook effect in cell assays.
“Regarding clinical applications, appropriate dosage may be an issue, as saturating doses of free PROTAC molecules can antagonize the binding of binary PROTAC-protein complexes to their ternary partner and abrogate catalytic degradation, a well-documented phenomenon known as the hook effect in cell assays 23,33,34 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [23]
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Cites
limma powers differential expression analyses for RNA-sequencing and microarray studies
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv007 · Cited by 40,458 · see citing works
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890 · 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
Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556 · 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
Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells
Boyer, L. A., Lee, T. I., Cole, M. F., Johnstone, S. E., Levine, S. S., Zucker, J. P., Guenther, M. G., Kumar, R. M., Murray, H. L., Jenner, R. G., et al. (2005) · Cell · doi:10.1016/j.cell.2005.08.020 · Cited by 4,505 · see citing works
Self-citationPhthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760 · see citing works
Self-citationMalumbres, M. (2014) · Genome biology · doi:10.1186/gb4184 · Cited by 1,683 · see citing works
Transcriptional 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-citationc-Myc Regulates Transcriptional Pause Release
Rahl, P. B., Lin, C. Y., Seila, A. C., Flynn, R. A., McCuine, S., Burge, C. B., Sharp, P. A., & Young, R. A. (2010) · Cell · doi:10.1016/j.cell.2010.03.030 · Cited by 1,279 · see citing works
Self-citationMcAlister, G. C., Nusinow, D. P., Jedrychowski, M. P., Wühr, M., Huttlin, E. L., Erickson, B. K., Rad, R., Haas, W., & Gygi, S. P. (2014) · Analytical Chemistry · doi:10.1021/ac502040v · Cited by 1,263 · see citing works
Self-citationHijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140 · see citing works
MS3 eliminates ratio distortion in isobaric multiplexed quantitative proteomics
Ting, L., Rad, R., Gygi, S. P., & Haas, W. (2011) · Nature Methods · doi:10.1038/nmeth.1714 · Cited by 1,009 · see citing works
Self-citationBharathavikru, S., & Dudnakova, T. (2016) · Cited by 953 · see citing works
Modular PROTAC design for the degradation of oncogenic BCR-ABL
Lai, A. C., Toure, M., Hellerschmied, D., Salami, J., Jaime‐Figueroa, S., Ko, E., Hines, J., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507634 · Cited by 618 · see citing works
Revisiting 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-citationIncreasing the Multiplexing Capacity of TMTs Using Reporter Ion Isotopologues with Isobaric Masses
McAlister, G. C., Huttlin, E. L., Haas, W., Ting, L., Jedrychowski, M. P., Rogers, J. C., Kuhn, K., Pike, I., Grothe, R. A., Blethrow, J. D., et al. (2012) · Analytical Chemistry · doi:10.1021/ac301572t · Cited by 605 · see citing works
Self-citationQuantitative ChIP-Seq normalization reveals global modulation of the epigenome
Orlando, D. A., Chen, M. W., Brown, V. E., Solanki, S., Choi, Y. J., Olson, E. R., Fritz, C. C., Bradner, J. E., & Guenther, M. G. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.018 · Cited by 503 · see citing works
Self-citationWinter, G. E., Mayer, A., Buckley, D. L., Erb, M. A., Roderick, J. E., Vittori, S., Reyes, J. M., di Iulio, J., Souza, A., Ott, C. J., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.004 · Cited by 465 · see citing works
Self-citationFlavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication
Chao, S., Fujinaga, K., Marion, J. E., Taube, R., Sausville, E. A., Senderowicz, A. M., Peterlin, B. M., & Price, D. H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000446200 · Cited by 456 · see citing works
Functional Interrogation of the Kinome Using Nucleotide Acyl Phosphates
Patricelli, M. P., Szardenings, A. K., Liyanage, M., Nomanbhoy, T. K., Wu, M., Weissig, H., Aban, A., Chun, D., Tanner, S. W., & Kozarich, J. W. (2006) · Biochemistry · doi:10.1021/bi062142x · Cited by 426 · see citing works
Self-citationYamada, T., Yamaguchi, Y., Inukai, N., Okamoto, S., Mura, T., & Handa, H. (2006) · Molecules and Cells · doi:10.1016/j.molcel.2005.11.024 · Cited by 421 · see citing works
Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors
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., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2166 · Cited by 374 · see citing works
Self-citationIn 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-citationWada, T., Takagi, T., Yamaguchi, Y., Watanabe, D., & Handa, H. (1998) · The EMBO Journal · doi:10.1093/emboj/17.24.7395 · Cited by 355 · 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-citationGilchrist, D. A., Nechaev, S., Lee, C., Ghosh, S., Collins, J. B., Li, L., Gilmour, D. S., & Adelman, K. (2008) · Genes & Development · doi:10.1101/gad.1643208 · Cited by 308 · see citing works
Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy
Sedlacek, H., Czech, J., Naik, R., Kaur, G., Worland, P., Losiewicz, M., Parker, B., Carlson, B., Smith, A., Senderowicz, A., et al. (1996) · International Journal of Oncology · doi:10.3892/ijo.9.6.1143 · Cited by 275 · see citing works
Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death
Chen, R., Keating, M. J., Gandhi, V. V., & Plunkett, W. K. (2005) · Blood · doi:10.1182/blood-2005-04-1678 · Cited by 261 · see citing works
Misra, R. N., Xiao, H., Kim, K. S., Lu, S., Han, W.-C., Barbosa, S. A. L., Hunt, J. T., Rawlins, D. B., Shan, W., Ahmed, S. Z., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm0305568 · Cited by 258 · see citing works
The cyclin‐dependent protein kinases and the control of cell division
Dorée, M., & Galas, S. (1994) · The FASEB Journal · doi:10.1096/fasebj.8.14.7958616 · Cited by 204 · see citing works
CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinomaPreprint
Huang, C., Lujambio, A., Zuber, J. A., Tschaharganeh, D. F., Doran, M. G., Evans, M. J., Kitzing, T. M., Zhu, N., de Stanchina, E., Sawyers, C. L., et al. (2014) · Genes & Development · doi:10.1101/gad.244368.114 · Cited by 201 · see citing works
König, A. A., Schwartz, G. K., Mohammad, R. M., Al-Katib, A. M., & Gabrilove, J. L. (1997) · Blood · doi:10.1182/blood.v90.11.4307 · Cited by 191 · see citing works
Identification of a Cyclin Subunit Required for the Function ofDrosophila P-TEFb
Peng, J., Marshall, N. F., & Price, D. H. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.22.13855 · Cited by 178 · see citing works
Hirose, Y., & Ohkuma, Y. (2007) · The Journal of Biochemistry · doi:10.1093/jb/mvm090 · Cited by 168 · see citing works
Poss, Z. C., Ebmeier, C. C., Odell, A. T., Tangpeerachaikul, A., Lee, T., Pelish, H. E., Shair, M. D., Dowell, R. D., Old, W. M., & Taatjes, D. J. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.030 · Cited by 160 · see citing works
Bonhoure, N., Bounova, G., Bernasconi, D., Praz, V., Lammers, F., Canella, D., Willis, I. M., Herr, W., Hernandez, N., Delorenzi, M., et al. (2014) · Genome Research · doi:10.1101/gr.168260.113 · Cited by 155 · see citing works
Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism
Lu, H., Xue, Y., Yu, G. K., Arias, C., Lin, J., Fong, S. K., Faure, M., Weisburd, B., Ji, X., Mercier, A., et al. (2015) · eLife · doi:10.7554/elife.06535 · Cited by 152 · see citing works
Cyclin-Dependent Kinase Inhibitors as Anticancer Drugs
Kryštof, V., & Uldrijan, S. (2010) · Current Drug Targets · doi:10.2174/138945010790711950 · Cited by 138 · see citing works
The transition from transcriptional initiation to elongation
Wade, J. T., & Struhl, K. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2007.12.008 · Cited by 117 · see citing works
Chemical inhibition of the TFIIH-associated kinase Cdk7/Kin28 does not impair global mRNA synthesis
Kanin, E. I., Kipp, R. T., Kung, C. K.-H., Slattery, M. G., Viale, A. J., Hahn, S., Shokat, K. M., & Ansari, A. Z. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611505104 · Cited by 111 · see citing works
Edwards, A., & Haas, W. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-3341-9_1 · Cited by 88 · see citing works
Self-citationRodríguez‐Molina, J. B., Tseng, S. C., Simonett, S. P., Taunton, J., & Ansari, A. Z. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.06.036 · Cited by 74 · see citing works
Pctaire1 Phosphorylates N-Ethylmaleimide-sensitive Fusion Protein
Liu, Y., Cheng, K., Gong, K., Fu, A. K. Y., & Ip, N. Y. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513496200 · Cited by 72 · see citing works
PFTK1 interacts with cyclin Y to activate non-canonical Wnt signaling in hepatocellular carcinoma
Sun, T., Co, N. N., & Wong, N. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.05.002 · Cited by 50 · see citing works
Mitra, P., Yang, R.-M., Sutton, J. C., Ramsay, R. G., & Gonda, T. J. (2016) · Oncotarget · doi:10.18632/oncotarget.6997 · Cited by 48 · see citing works
Nomanbhoy, T. K., Sharma, G., Brown, H., Wu, J., Aban, A., Vogeti, S., Alemayehu, S., Sykes, M., Rosenblum, J. S., & Kozarich, J. W. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00629 · Cited by 31 · see citing works
Self-citationTBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription
Okuda, H., Takahashi, S., Takaori-Kondo, A., & Yokoyama, A. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1222337 · Cited by 26 · see citing works
Samarakkody, A. S., Abbas, A., Scheidegger, A., Warns, J. A., Nnoli, O., Jokinen, B., Zarns, K., Kubat, B., Dhasarathy, A., & Nechaev, S. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv263 · Cited by 23 · see citing works
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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-citationTargeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · see citing works
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Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 818 · see citing works
A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
Bai, L., Zhou, H., Xu, R., Zhao, Y., Chinnaswamy, K., McEachern, D., Chen, J., Yang, C.-Y., Liu, Z., Wang, M., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.10.002 · Cited by 652 · see citing works
“The classical “hook effect” for PROTAC degraders (Bondeson et al., 2015; Burslem et al., 2018a; Chan et al., 2018; Farnaby et al., 2019; Lu et al., 2015; Olson et al., 2018; Schiedel et al., 2018; Winter et al., 2017) was not observed for SD-36 at concentrations as high as 10 μM in all the cell lines tested (Figure 2A…”
BackgroundPROTACs: great opportunities for academia and industry
Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y.-G., Tong, Y., & Rao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0101-6 · Cited by 651 · see citing works
Targeted protein degradation: elements of PROTAC design
Paiva, S.-L., & Crews, C. M. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.02.022 · Cited by 586 · see citing works
Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulationPreprint
Core, L. J., & Adelman, K. (2019) · Genes & Development · doi:10.1101/gad.325142.119 · Cited by 560 · see citing works
A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader
Huang, H.-T., Dobrovolsky, D., Paulk, J., Yang, G., Weisberg, E. L., Doctor, Z. M., Buckley, D. L., Cho, J.-H., Ko, E., Jang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.10.005 · Cited by 437 · see citing works
Self-citationEdmondson, S. D., Yang, B., & Fallan, C. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.04.030 · Cited by 422 · see citing works
Proteolysis-targeting chimeras (PROTACs) in cancer therapy
Li, X., Pu, W., Zheng, Q., Ai, M., Chen, S., & Peng, Y. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01434-3 · Cited by 374 · see citing works
“CDK2/5 [84], CDK8 [112], CDK9 [38, 114, 115, 117, 159], Cdc20 [119], c-Met [79], CREPT [121], CYP1B1 [122], DHODH [123], ER [89, 124, 126, 128, 160], ERK1/2 [26], FLT-3 [132, 161], HER2 [79], MEK1/2 [85, 86, 162], KRASG12C [87, 163], GSPT1 [125], PLK1 [127], SLC9A1 [129], TACC3 [130], TRIM24 [131], TRKA/C [133, 164],…”
BackgroundAn, S., & Fu, L. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.005 · Cited by 363 · see citing works
“However, small-molecule PROTACs catalytically involve in multiple rounds of target protein degradation [33,43,47].”
BackgroundInfluentialMapping the Degradable Kinome Provides a Resource for Expedited Degrader Development
Donovan, K. A., Ferguson, F. M., Bushman, J. W., Eleuteri, N. A., Bhunia, D., Ryu, S., Tan, L., Shi, K., Yue, H., Liu, X., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.038 · Cited by 359 · see citing works
Self-citationHines, J., Lartigue, S., Dong, H., Qian, Y., & Crews, C. M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2918 · Cited by 348 · see citing works
“both contexts – the research lab and the clinic -- PROTACs have received recent attention, leading to the generation of PROTACs that degrade cyclin-dependent kinases (12), lipid kinases (13), peptidases (4), protein isomerases (5), scaffolding proteins (13), transcription factors (3,11,14), protein kinases (1,10,15-18…”
PHOTACs enable optical control of protein degradation
Reynders, M., Matsuura, B. S., Bérouti, M., Simoneschi, D., Marzio, A., Pagano, M., & Trauner, D. H. (2020) · Science Advances · doi:10.1126/sciadv.aay5064 · Cited by 333 · see citing works
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Wang, Y., Jiang, X., Feng, F., Liu, W., & Sun, H. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.08.001 · Cited by 335 · see citing works
Zoppi, V., Hughes, S. J., Maniaci, C., Testa, A., Gmaschitz, T., Wieshofer, C., Koegl, M., Riching, K. M., Daniels, D. L., Spallarossa, A., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01413 · Cited by 336 · see citing works
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Riching, K. M., Mahan, S. D., Corona, C. R., McDougall, M. G., Vasta, J. D., Robers, M. B., Urh, M., & Daniels, D. L. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00692 · Cited by 307 · see citing works
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Nabet, B., Ferguson, F. M., Seong, B. K. A., Kuljanin, M., Leggett, A. L., Mohardt, M. L., Robichaud, A., Conway, A. S., Buckley, D. L., Mancias, J. D., et al. (2020) · doi:10.1101/2020.03.13.980946 · Cited by 312 · see citing works
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Pfaff, P., Samarasinghe, K. T. G., Crews, C. M., & Carreira, E. M. (2019) · ACS Central Science · doi:10.1021/acscentsci.9b00713 · Cited by 314 · see citing works
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Cao, C., He, M., Wang, L., He, Y., & Rao, Y. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00220e · Cited by 313 · see citing works
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Zou, Y., Ma, D., & Wang, Y. (2019) · Cell Biochemistry and Function · doi:10.1002/cbf.3369 · Cited by 307 · see citing works
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“…process of opto-pomalidomide could also be applied to any other pomalidomide-derived PROTACs for controllable degradation of protein targets such as cyclin-dependent kinases ( 29 , 30 ), breakpoint cluster region protein (BCR)–ABL ( 31 ), Bruton’s tyrosine kinase ( 32 ), and Tau ( 33 ).”
Self-citationTarget and tissue selectivity of PROTAC degraders
Guenette, R. G., Yang, S. W., Min, J., Pei, B., & Potts, P. R. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00200k · Cited by 324 · 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
“These compounds consist of a CDK-binding ligand (SNS-032) linked to a thalidomide derivative that binds to the E3 ubiquitin ligase Cereblon to promote degradation (137).”
BackgroundExploring Targeted Degradation Strategy for Oncogenic KRASG12C
Zeng, M., Xiong, Y., Safaee, N., Nowak, R. P., Donovan, K. A., Yuan, C. J., Nabet, B., Gero, T. W., Feru, F., Li, L., et al. (2020) · Cell Chemical Biology · doi:10.1016/j.chembiol.2019.12.006 · Cited by 275 · see citing works
Self-citationDhimolea, E., Simoes, R. D. M., Kansara, D. N., Al’Khafaji, A. M., Bouyssou, J., Weng, X., Sharma, S., Raja, J., Awate, P., Shirasaki, R., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.12.002 · Cited by 260 · see citing works
Self-citationZeng, S., Huang, W., Zheng, X., Cheng, L., Zhang, Z., Wang, J., & Shen, Z. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112981 · Cited by 262 · see citing works
Self-citationDevelopment of dual and selective degraders of cyclin-dependent kinases 4 and 6
Jiang, B., Wang, E. S., Donovan, K. A., Liang, Y., Fischer, E. S., Zhang, T., & Gray, N. S. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201901336 · Cited by 272 · see citing works
Self-citationHomolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML
Brand, M., Jiang, B., Bauer, S., Donovan, K. A., Liang, Y., Wang, E. S., Nowak, R. P., Yuan, J. C., Zhang, T., Kwiatkowski, N., et al. (2019) · Cell Chemical Biology · doi:10.1016/j.chembiol.2018.11.006 · Cited by 258 · see citing works
“Interestingly, studies of degraders derived from multi-targeted warheads revealed that only a subset of targets were efficiently degraded, indicating the possibility of engineering selectivity into polypharmacologic scaffolds (Bondeson et al., 2017; Gadd et al., 2017; Huang et al., 2017; Olson et al., 2017; Winter et…”
BackgroundMethodSelf-citationTrivalent PROTACs enhance protein degradation via combined avidity and cooperativity
Imaide, S., Riching, K. M., Makukhin, N., Vetma, V., Whitworth, C., Hughes, S. J., Trainor, N., Mahan, S. D., Murphy, N., Cowan, A. D., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00878-4 · Cited by 251 · see citing works
de Wispelaere, M., Du, G., Donovan, K. A., Zhang, T., Eleuteri, N. A., Yuan, J. C., Kalabathula, J., Nowak, R. P., Fischer, E. S., Gray, N. S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11429-w · Cited by 237 · see citing works
Self-citationProteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK)
Zhang, C., Han, X.-R., Yang, X., Jiang, B., Liu, J., Xiong, Y., & Jin, J. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.03.071 · Cited by 226 · see citing works
“pan kinase PROTACs [33, 34], most of kinase PROTACs reported to date target specific kinases, such as RIPK2 [35], BCR-ABL [36, 37], CDK9 [38, 39], TBK1 [40], FLT3 [33], BTK [33], EGFR [41], HER2 [41], and c-Met [41].”
BackgroundInfluentialSelf-citationOptical Control of Small Molecule-Induced Protein Degradation
Naro, Y., Darrah, K. E., & Deiters, A. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.9b12718 · Cited by 226 · see citing works
Proteolysis‐targeting chimeras in drug development: A safety perspective
Moreau, K., Coen, M., Zhang, A. X., Pachl, F., Castaldi, M. P., Dahl, G., Boyd, H., Scott, C., & Newham, P. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15014 · Cited by 229 · see citing works
“Global proteomics techniques have been broadly applied in the PROTAC field (Bondeson et al., 2018; Donovan et al., 2018; Farnaby et al., 2019; Huang et al., 2018; Olson et al., 2018) as a way to measure degradation selectivity as well as identifying previ-”
MethodPotent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders
Su, S., Yang, Z., Gao, H., Yang, H., Zhu, S., An, Z., Wang, J., Li, Q., Chandarlapaty, S., Deng, H., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00871 · Cited by 209 · 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
Cecchini, C., Pannilunghi, S., Tardy, S., & Scapozza, L. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.672267 · Cited by 198 · see citing works
“Being an intrinsic event in PROTAC pharmacology, the hook effect is difficult to avoid and often occurs at concentrations in the range of 1–10μM, which are typically applied to test small molecules in vitro (Chan et al., 2018; Olson et al., 2018; Anderson et al., 2020; Shah et al., 2020; Yang et al., 2020; Zhang et al…”
BackgroundCheng, M., Yu, X., Lu, K. J., Xie, L., Wang, L., Meng, F., Han, X., Chen, X., Liu, J., Xiong, Y., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01566 · Cited by 197 · see citing works
Emerging New Concepts of Degrader Technologies
Ding, Y., Fei, Y., & Lu, B. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.04.005 · Cited by 204 · see citing works
“One desirable property of PROTACs is that they are catalytically involved in multiple rounds of target protein degradation [29,32,33].”
BackgroundPROTACs to address the challenges facing small molecule inhibitors
Martín-Acosta, P., & Xiao, X. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112993 · Cited by 186 · see citing works
Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule
Zhao, Q., Lan, T., Su, S., & Rao, Y. (2018) · Chemical Communications · doi:10.1039/c8cc07813k · Cited by 185 · see citing works
Harnessing the Power of Proteolysis for Targeted Protein Inactivation
Verma, R., Mohl, D., & Deshaies, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.010 · Cited by 185 · see citing works
E3 ligase ligand chemistries: from building blocks to protein degraders
Sosič, I., Bricelj, A., & Steinebach, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00148a · Cited by 173 · see citing works
Rewiring cancer drivers to activate apoptosis
Gourisankar, S. P., Krokhotin, A., Ji, W., Liu, X., Chang, C.-Y., Kim, S. H., Li, Z., Wenderski, W., Simanauskaite, J., Yang, H., et al. (2023) · Nature · doi:10.1038/s41586-023-06348-2 · Cited by 172 · see citing works
Self-citationNELF Regulates a Promoter-Proximal Step Distinct from RNA Pol II Pause-Release
Aoi, Y., Smith, E. R., Shah, A. P., Rendleman, E. J., Marshall, S. A., Woodfin, A. R., Chen, F., Shiekhattar, R., & Shilatifard, A. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.02.014 · Cited by 164 · see citing works
“To exclude potential off-target effects of flavopiridol, we also tested the effects of NVP-2, a highly selective P-TEFb inhibitor with sub-nanomolar potency (Olson et al., 2018).”
BackgroundIshoey, M., Chorn, S., Singh, N., Jaeger, M. G., Brand, M., Paulk, J., Bauer, S., Erb, M. A., Parapatics, K., Müller, A. C., et al. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.7b00969 · Cited by 177 · see citing works
Self-citationPROTACs– a game-changing technology
Konstantinidou, M., Li, J., Zhang, B., Wang, Z., Shaabani, S., ter Brake, F., Essa, K., & Dömling, A. S. S. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1659242 · Cited by 167 · see citing works
“Since then, PROTACs with IMiD small molecules targeting CRBN and diverse proteins of interest, including the bromodomain and extra-Terminal (BET) proteins (BRD2/3/4) [16–18], FKBP12 [16], BCR-ABL [19], BRD9 [20], Sirt2 [21], CDK9 [22,23], FLT3 [24], BTK [24,25], ALK [26], CDK4/CDK6 [27,28] and HDAC6 [29] have been rep…”
BackgroundTargeted degradation of the enhancer lysine acetyltransferases CBP and p300
Vannam, R., Sayilgan, J., Ojeda, S., Karakyriakou, B., Hu, E., Kreuzer, J., Morris, R., Herrera Lopez, X. I., Rai, S., Haas, W., et al. (2021) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.12.004 · Cited by 177 · see citing works
Self-citationBruton tyrosine kinase degradation as a therapeutic strategy for cancer
Dobrovolsky, D., Wang, E. S., Morrow, S., Leahy, C., Faust, T., Nowak, R. P., Donovan, K. A., Yang, G., Li, Z., Fischer, E. S., et al. (2019) · Blood · doi:10.1182/blood-2018-07-862953 · Cited by 169 · see citing works
Self-citationTargeting 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-citationDiscovery of a first-in-class CDK2 selective degrader for AML differentiation therapy
Wang, L., Shao, X., Zhong, T., Wu, Y., Xu, A., Sun, X., Gao, H., Liu, Y., Lan, T., Tong, Y., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00742-5 · Cited by 161 · see citing works
Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs
Girardini, M., Maniaci, C., Hughes, S. J., Testa, A., & Ciulli, A. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.02.048 · Cited by 157 · see citing works
Targeted protein degradation: current and future challenges
Hanzl, A., & Winter, G. E. (2020) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.11.012 · Cited by 157 · see citing works
Self-citationThe role of reversible and irreversible covalent chemistry in targeted protein degradation
Kiely‐Collins, H., Winter, G. E., & Bernardes, G. J. L. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.03.005 · Cited by 156 · see citing works
“targets including kinases (Bondeson et al., 2015; Buhimschi et al., 2018; Cromm et al., 2018; Olson et al., 2018; Powell et al., 2018; Sun et al., 2018), bromodomains (Bai et al.”
BackgroundSelf-citationRationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta
Bai, N., Miller, S. A., Andrianov, G. V., Yates, M., Kirubakaran, P., & Karanicolas, J. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c01451 · Cited by 157 · see citing works
Developments of CRBN-based PROTACs as potential therapeutic agents
Wang, C., Zhang, Y., Wu, Y., & Xing, D. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113749 · Cited by 152 · see citing works
Anshabo, A. T., Milne, R. W., Wang, S., & Albrecht, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.678559 · Cited by 152 · see citing works
Discovery 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-citationJang, J., To, C., Clercq, D. J. H. D., Park, E., Ponthier, C. M., Shin, B. H., Mushajiang, M., Nowak, R. P., Fischer, E. S., Eck, M. J., et al. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202003500 · Cited by 151 · see citing works
Self-citationExpanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation
Kannt, A., & Đikić, I. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.007 · Cited by 148 · see citing works
The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination
Jin, J., Wu, Y., Chen, J., Shen, Y., Zhang, L., Zhang, H., Chen, L., Yuan, H., Chen, H., Zhang, W., et al. (2020) · Theranostics · doi:10.7150/thno.46985 · Cited by 146 · see citing works
“PROTAC: PROteolysis TArgeting Chimera; pPROTAC: peptide PROTAC; POI: protein of interest; CLL: chronic lymphocytic leukemia; BTK: Bruton's tyrosine kinase; UPS: ubiquitin-proteasome system; ER: estrogen receptor; AR: androgen receptor; BRD4: bromodomain-containing protein 4; ALK: anaplastic lymphoma kinase; CDK9: cycl…”
BackgroundDiscovery of Wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity
Bian, J., Ren, J., Li, Y., Wang, J., Xu, X., Feng, Y., Tang, H., Wang, Y., & Li, Z. (2018) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2018.08.028 · Cited by 140 · see citing works
A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
Bery, N., Miller, A., & Rabbitts, T. (2020) · Nature Communications · doi:10.1038/s41467-020-17022-w · Cited by 132 · see citing works
Selective Mediator dependence of cell-type-specifying transcription
Jaeger, M. G., Schwalb, B., Mackowiak, S. D., Velychko, T., Hanzl, A., Imrichová, H., Brand, M., Agerer, B., Chorn, S., Nabet, B., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0635-0 · Cited by 132 · see citing works
Self-citationDiscovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling
You, I., Erickson, E. C., Donovan, K. A., Eleuteri, N. A., Fischer, E. S., Gray, N. S., & Toker, A. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.11.014 · Cited by 132 · see citing works
Self-citationTargeting CDK9 for Anti-Cancer Therapeutics
Mandal, R., Becker, S., & Strebhardt, K. (2021) · Cancers · doi:10.3390/cancers13092181 · Cited by 132 · see citing works
The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells
Kurimchak, A. M., Herrera-Montávez, C., Montserrat-Sangrà, S., Araiza-Olivera, D., Hu, J., Neumann-Domer, R., Kuruvilla, M., Bellacosa, A., Testa, J. R., Jin, J., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abn2707 · Cited by 136 · see citing works
Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
Hanzl, A., Casement, R., Imrichova, H., Hughes, S. J., Barone, E., Testa, A., Bauer, S., Wright, J., Brand, M., Ciulli, A., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-022-01177-2 · Cited by 133 · see citing works
“Simultaneously, it led to a marked sensitization (15-fold shift in EC 50 ) to the CDK9-targeting PROTAC THAL-SNS-032 40 (Extended Data Fig.”
Self-citationSolvent-Induced Protein Precipitation for Drug Target Discovery on the Proteomic Scale
Zhang, X., Wang, Q., Li, Y., Ruan, C., Wang, S., Hu, L., & Ye, M. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b04531 · Cited by 119 · see citing works
Molecular mechanisms of thalidomide and its derivatives
Ito, T., & Handa, H. (2020) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.96.016 · Cited by 121 · see citing works
Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update
Wu, T., Qin, Z., Tian, Y., Wang, J., Xu, C., Li, Z., & Bian, J. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00744 · Cited by 120 · see citing works
Mayor-Ruiz, C., Jaeger, M. G., Bauer, S., Brand, M., Sin, C., Hanzl, A., Mueller, A. C., Menche, J., & Winter, G. E. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.013 · Cited by 119 · see citing works
Self-citationBivalent Ligands for Protein Degradation in Drug Discovery
Scheepstra, M., Hekking, K. F. W., Hijfte, L. V., & Folmer, R. H. A. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.01.006 · Cited by 120 · see citing works
“[96] Olson CM, Jiang B, Erb MA, Liang Y, Doctor ZM, Zhang Z, et al. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation.”
BackgroundInfluentialStrategies for designing proteolysis targeting chimaeras (PROTACs)
He, S., Dong, G., Cheng, J., Wu, Y., & Sheng, C. (2022) · Medicinal Research Reviews · doi:10.1002/med.21877 · Cited by 118 · see citing works
“However, in some cases, selective POI ligands may not yield selective degraders.(168) In addition, reasonable adjustment of the linker length in PROTACs has an important effect on the selectivity towards homologous proteins.”
BackgroundShirasaki, R., Matthews, G. M., Gandolfi, S., de Matos Simoes, R., Buckley, D. L., Raja Vora, J., Sievers, Q. L., Brüggenthies, J. B., Dashevsky, O., Poarch, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108532 · Cited by 123 · see citing works
Self-citationDevelopment of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins
Ohoka, N., Tsuji, G., Shoda, T., Fujisato, T., Kurihara, M., Demizu, Y., & Naito, M. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00704 · Cited by 117 · see citing works
Development of selective mono or dual PROTAC degrader probe of CDK isoforms
Zhou, F., Chen, L., Cao, C.-G., Yu, J., Luo, X., Zhou, P., Zhao, L., Du, W., Cheng, J., Xie, Y., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.111952 · Cited by 118 · see citing works
Qiu, X., Li, Y., Yu, B., Ren, J., Huang, H., Wang, M., Ding, H., Li, Z., Wang, J., & Bian, J. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.113091 · Cited by 117 · see citing works
Wang, Z., He, N., Guo, Z., Niu, C., Song, T., Guo, Y., Cao, K., Wang, A., Zhu, J., Zhang, X., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00919 · Cited by 120 · see citing works
Self-citationA Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
Tong, B., Spradlin, J. N., Novaes, L. F. T., Zhang, E., Hu, X., Moeller, M., Brittain, S. M., McGregor, L. M., McKenna, J. M., Tallarico, J. A., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00348 · Cited by 118 · see citing works
PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy
Kelm, J. M., Pandey, D. S., Malin, E., Kansou, H. W., Arora, S., Kumar, R., & Gavande, N. S. (2023) · Molecular Cancer · doi:10.1186/s12943-022-01707-5 · Cited by 115 · see citing works
Large-scale discovery of male reproductive tract-specific genes through analysis of RNA-seq datasets
Robertson, M. J., Kent, K., Tharp, N., Nozawa, K., Dean, L., Mathew, M., Grimm, S. L., Yu, Z., Légaré, C., Fujihara, Y., et al. (2020) · BMC Biology · doi:10.1186/s12915-020-00826-z · Cited by 109 · see citing works
Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export
Duan, L., Zaepfel, B. L., Aksenova, V., Dasso, M., Rothstein, J. D., Kaláb, P., & Hayes, L. R. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111106 · Cited by 109 · see citing works
“To confirm that TDP-43 nuclear localization is sensitive to inhibition of mRNA synthesis and avoid off-target effects of DNA intercalation, we treated HeLa cells with NVP2, an inhibitor of CDK9-dependent RNA pol II activation (Olson et al., 2018), and monitored TDP-43 localization by immunofluorescence (IF) (Figures 1…”
MethodXie, S., Zhu, J., Li, J., Zhan, F., Yao, H., Xu, J., & Xu, S. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00736 · Cited by 109 · see citing works
Annual review of PROTAC degraders as anticancer agents in 2022
Wang, X., Qin, Z.-L., Li, N., Jia, M.-Q., Liu, Q.-G., Bai, Y., Song, J., Yuan, S., & Zhang, S. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116166 · Cited by 107 · see citing works
Development and Characterization of a Wee1 Kinase Degrader
Li, Z., Pinch, B. J., Olson, C. M., Donovan, K. A., Nowak, R. P., Mills, C. E., Scott, D. A., Doctor, Z. M., Eleuteri, N. A., Chung, M., et al. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.10.013 · Cited by 107 · see citing works
“, 2019), and selective degradation of CDK9 is possible with degraders based on a non-selective CDK inhibitor(Olson et al., 2017).”
BackgroundMethodSelf-citationSPT5 stabilization of promoter-proximal RNA polymerase II
Aoi, Y., Takahashi, Y.-H., Shah, A. P., Iwanaszko, M., Rendleman, E. J., Khan, N. H., Cho, B.-K., Goo, Y. A., Ganesan, S., Kelleher, N. L., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.006 · Cited by 107 · see citing works
Targeted protein degradation directly engaging lysosomes or proteasomes
Kim, J., Byun, I., Kim, D. Y., Joh, H., Kim, H. J., & Lee, M. J. (2024) · Chemical Society Reviews · doi:10.1039/d3cs00344b · Cited by 106 · see citing works
Therapeutic 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
“NVP-2 is an aminopyrimidine-based inhibitor developed by Novartis and was recently shown to have sub-nanomolar potency towards CDK9/CycT and good selectivity against a panel of 468 kinases (Kinomescan), with ≥ 700-fold lower activity against DYRK1B and CDK7 [82].”
BackgroundInfluentialDiscovery of potent small molecule PROTACs targeting mutant EGFR
Zhao, H., Yang, X., Lei, H., Xi, X.-X., Lu, S., Zhang, J., Xin, M., & Zhang, S. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112781 · Cited by 105 · see citing works
Dissecting 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
Discovery of a large-scale, cell-state-responsive allosteric switch in the 7SK RNA using DANCE-MaP
Olson, S. W., Turner, A. W., Arney, J. W., Saleem, I., Weidmann, C. A., Margolis, D. M., Weeks, K. M., & Mustoe, A. M. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.02.009 · 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
Röschert, I., Poon, E., Henssen, A. G., García, H. D., Gatti, M., Giansanti, C., Jamin, Y., Ade, C. P., Gallant, P., Schülein‐Völk, C., et al. (2021) · Nature Cancer · doi:10.1038/s43018-020-00171-8 · Cited by 96 · 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
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins
Lin, J., Jin, J., Shen, Y., Zhang, L., Gong, G., Bian, H., Chen, H., Nagle, D. G., Wu, Y., Zhang, W., et al. (2021) · Theranostics · doi:10.7150/thno.62686 · Cited by 98 · see citing works
PROTAC degraders as chemical probes for studying target biology and target validation
Němec, V., Schwalm, M. P., Müller, S., & Knapp, S. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00478j · Cited by 98 · see citing works
Critical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality
Kostić, M., & Jones, L. H. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.02.006 · Cited by 96 · see citing works
“Bcr-Abl tyrosine kinase [24], anaplastic lymphoma kinase (ALK) [25] [26], receptor tyrosine kinases [27], and cyclin-dependent kinases like CDK4 and/or 6 [28]–[30] and CDK9 [31] [32], as well as epigenetic targets [18], [19], [33]–[35] (for an up-to date and exhaustive list of available PROTACs please refer to [36]).”
BackgroundNovel immunomodulatory drugs and neo-substrates
Gao, S., Wang, S., & Song, Y. (2020) · Biomarker Research · doi:10.1186/s40364-020-0182-y · Cited by 95 · see citing works
Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader
Tovell, H., Testa, A., Zhou, H., Shpiro, N., Crafter, C., Ciulli, A., & Alessi, D. R. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00505 · Cited by 95 · see citing works
- Authors
- Olson, C. M., Jiang, B., Erb, M. A., Liang, Y., Doctor, Z. M., Zhang, Z., Zhang, T., Kwiatkowski, N., Boukhali, M., Green, J. L., Haas, W., Nomanbhoy, T., Fischer, E. S., Young, R. A., Bradner, J. E., Winter, G. E., & Gray, N. S.
- Affiliations
- Harvard University (US)
- California Sea Grant (US)
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Gray, Nathanael S
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2017-12-18
- Volume
- 14
- Issue
- 2
- Pages
- 163-170
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5912898
- OpenAlex
- W2781383440
- Cited by
- 552
- References
- 49
- Citations by year
- 2026: 41 · 2025: 78 · 2024: 71 · 2023: 63 · 2022: 69 · 2021: 77 · 2020: 77 · 2019: 51 · 2018: 24 · 2017: 1
- FWCI
- 17.42
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- PMC
- Funders
- National Cancer Institute (R01CA179483, R01CA218278)
- National Institute of General Medical Sciences (T32GM007753)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- CDK9, transcription elongation, CDK9 inhibitor, SNS-032, cereblon, E3 ubiquitin ligase, apoptosis, transcriptional dysregulation, cancer therapy
- MeSH terms
- Humans, Ligands, Oxazoles, Peptide Hydrolases, Phosphorylation, Protein Binding, Protein Conformation, Thalidomide, Thiazoles, Apoptosis, Crystallography, X-Ray, Inhibitory Concentration 50, Proteomics, Cyclin-Dependent Kinase 9, Ubiquitin-Protein Ligases, Cell Line, Tumor, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Cell Proliferation
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