The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
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.
Overview
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
Verification
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?
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
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
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
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
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
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn923 · Cited by 14,108
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
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
Self-citationMalumbres, M. (2014) · Genome biology · doi:10.1186/gb4184 · Cited by 1,730
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 1,543
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
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–200 of 575
Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8
Hatcher, J. M., Wang, E. S., Johannessen, L. H., Kwiatkowski, N. P., Sim, T., & Gray, N. S. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.8b00011 · Cited by 94
Self-citationP-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress
Bugai, A., Quaresma, A. J. C., Friedel, C. C., Lenasi, T., Düster, R., Sibley, C. R., Fujinaga, K., Kukanja, P., Hennig, T., Blasius, M., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.01.033 · Cited by 92
Qiu, Z., Zhao, L., Shen, J., Liang, Z., Wu, Q., Yang, K., Min, L., Gimple, R. C., Yang, Q., Bhargava, S., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1848 · Cited by 90
Protein degradation technology: a strategic paradigm shift in drug discovery
Li, H., Dong, J., Cai, M., Xu, Z., Cheng, X., & Qin, J. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01146-7 · Cited by 96
Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers
Sulahian, R., Kwon, J. J., Walsh, K. H., Pailler, E., Bosse, T. L., Thaker, M., Almanza, D., Dempster, J. M., Pan, J., Piccioni, F., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.090 · Cited by 90
“Achievement of small molecules that bind SHOC2 could enable ligand-mediated protein degradation approaches for therapeutic development (Lu et al., 2014; Olson et al., 2018; Winter et al., 2015).”
BackgroundSelf-citationCao, C.-G., Yang, J., Chen, Y. X., Zhou, P., Wang, Y., Du, W., Zhao, L., & Chen, Y. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00821 · Cited by 88
Expanding the role of proteasome homeostasis in Parkinson’s disease: beyond protein breakdown
Bi, M., Du, X., Jiao, Q., Chen, X., & Jiang, H. F. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03441-0 · Cited by 91
An overview of kinase downregulators and recent advances in discovery approaches
Wang, B., Wu, H., Hu, C., Wang, H., Liu, J., Wang, W., & Liu, Q. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00826-7 · Cited by 93
Proteolysis targeting chimeras (PROTACs) in cancer therapy
Ocaña, A., & Pandiella, A. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01672-1 · Cited by 89
Acetylation of histone H2B marks active enhancers and predicts CBP/p300 target genes
Narita, T., Higashijima, Y., Kilic, S., Liebner, T., Walter, J., & Choudhary, C. (2023) · Nature Genetics · doi:10.1038/s41588-023-01348-4 · Cited by 97
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
“CDK9 is a core component of the P-TEFb transcription elongation complex and is required for all active transcription (Olson et al., 2018; Rahl et al., 2010; Winter et al., 2017).”
BackgroundSelf-citationLi, J., Liu, T., Song, Y., Wang, M., Liu, L., Zhu, H., Li, Q., Lin, J. H., Jiang, H., Chen, K., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00257 · Cited by 89
Targeting Biomolecular Condensation and Protein Aggregation against Cancer
Silva, J. L., Foguel, D., Ferreira, V. F., Vieira, T. C. R. G., Marques, M. A., Ferretti, G. D. S., Outeiro, T. F., Cordeiro, Y., & de Oliveira, G. A. P. (2023) · Chemical Reviews · doi:10.1021/acs.chemrev.3c00131 · Cited by 86
Piperlongumine conjugates induce targeted protein degradation
Pei, J., Xiao, Y., Liu, X., Hu, W., Sobh, A., Yuan, Y., Zhou, S., Hua, N., Mackintosh, S. G., Zhang, X., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.01.004 · Cited by 87
Development of CDK2 and CDK5 Dual Degrader TMX‐2172
Teng, M., Jiang, J., He, Z., Kwiatkowski, N. P., Donovan, K. A., Mills, C. E., Victor, C., Hatcher, J. M., Fischer, E. S., Sorger, P. K., et al. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202004087 · Cited by 82
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 89
The GCN5: its biological functions and therapeutic potentials
Haque, M. E., Jakaria, M., Akther, M., Cho, D.-Y., Kim, I., & Choi, D. (2021) · Clinical Science · doi:10.1042/cs20200986 · Cited by 83
Core transcriptional regulatory circuitries in cancer
Chen, Y., Xu, L., Lin, R. Y., Müschen, M., & Koeffler, H. P. (2020) · Oncogene · doi:10.1038/s41388-020-01459-w · Cited by 80
Relocalizing transcriptional kinases to activate apoptosis
Sarott, R. C., Gourisankar, S. P., Karim, B. A., Nettles, S. A., Yang, H., Dwyer, B. G., Simanauskaite, J., Tse, J., Abuzaid, H. Z., Krokhotin, A., et al. (2024) · Science · doi:10.1126/science.adl5361 · Cited by 80
“This contrasted with optimized CDK9 degraders and inhibitors, which broadly inhibit transcription ( 8 ) and are similarly potent in both primary lymphocytes and DLBCL cells (Fig.”
BackgroundSelf-citationAntiviral PROTACs: Opportunity borne with challenge
Liang, J., Wu, Y., Lan, K., Dong, C., Wu, S., Li, S., & Zhou, H. (2023) · Cell Insight · doi:10.1016/j.cellin.2023.100092 · Cited by 76
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 74
Blake, D. R., Vaseva, A. V., Hodge, R. G., Kline, M. P., Gilbert, T. S. K., Tyagi, V., Huang, D., Whiten, G. C., Larson, J. E., Wang, X., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aav7259 · Cited by 71
Han, B. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014715 · Cited by 72
“In comparison, the dose-response curve of the ternary complex shows the hook effect, or a bell-shaped curve reaching a maximum at certain ligand concentration but falling back down to baseline level at sufficiently high concentrations (12, 25 – 32).”
Wei, D., Wang, H., Zeng, Q., Wang, W., Hao, B., Feng, X., Wang, P., Song, N., Kan, W., Huang, G., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01350 · Cited by 72
Tan, X., Huang, Z., Pei, H., Jia, Z., & Zheng, J. (2024) · iScience · doi:10.1016/j.isci.2024.110712 · Cited by 66
“48 However, though the occurrence of the ‘‘hook effect’’ has been observed in in-vitro studies, 49–51 resulting in a decreased efficiency of the PROTACs, ‘‘hook effect’’ has not been observed in in-vivo studies.”
BackgroundThe Renaissance of Cyclin Dependent Kinase Inhibitors
Ettl, T., Schulz, D., & Bauer, R. J. (2022) · Cancers · doi:10.3390/cancers14020293 · Cited by 71
“Prodrug 11 CDK2/4/6 [48] Pal-pom CDK4/6 [49] BSJ-03-123 CDK4/6 [50] PROTAC 6 CDK6 [51] CP-10 CDK6 [52] YX-2-107 CDK6 [53] CST651 CDK6 [54] JH-XI-10-02 CDK8 [55] PROTAC 3 CDK9 [56] PROTAC 11c CDK9 [57] B03 CDK9 [58] THAL-SNS-032 CDK9 [59] F3 CDK9/CDK2 [60]”
Chen, S., Cui, J., Chen, H., Yu, B., & Long, S. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115911 · Cited by 70
ASF1B promotes cervical cancer progression through stabilization of CDK9
Liu, X., Song, J., Zhang, Y., Wang, H., Sun, H., Feng, X., Hou, M., Chen, G., Tang, Q., & Ji, M. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-02872-5 · Cited by 69
Regulation of Promoter Proximal Pausing of RNA Polymerase II in Metazoans
Dollinger, R., & Gilmour, D. S. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.166897 · Cited by 75
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
Monitoring and deciphering protein degradation pathways inside cells
Daniels, D. L., Riching, K. M., & Urh, M. (2018) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2018.12.001 · Cited by 65
Poon, E., Liang, T., Jamin, Y., Walz, S., Kwok, C., Hakkert, A., Barker, K. T., Urban‐Wójciuk, Z., Thway, K., Zeid, R., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci134132 · Cited by 69
“Finally, we observed that only in CDK2-knockout cells did compound 3 treatment or CDK9 degradation using THAL-SNS-032 (27) (a potent and selective CDK9 degrading PROTAC) result in an increase in sub-G1 apoptotic cells (Supplemental Figure 4, F and G) and growth inhibitory effects (Figure 2E).”
BackgroundMethodInfluentialSelf-citationTransforming targeted cancer therapy with PROTACs: A forward-looking perspective
Farnaby, W., Koegl, M., McConnell, D. B., & Ciulli, A. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.02.009 · Cited by 66
Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2
Du, G., Jiang, J., Wu, Q., Henning, N. J., Donovan, K. A., Yue, H., Che, J., Lu, W., Fischer, E. S., Bardeesy, N. M., et al. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202101328 · Cited by 66
Self-citationA MedChem toolbox for cereblon-directed PROTACs
Steinebach, C., Sosič, I., Lindner, S., Bricelj, A., Kohl, F., Ng, Y. L. D., Monschke, M., Wagner, K. G., Krönke, J., & Gütschow, M. (2019) · MedChemComm · doi:10.1039/c9md00185a · Cited by 66
Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery
Pei, H., Peng, Y., Zhao, Q., & Chen, Y. (2019) · RSC Advances · doi:10.1039/c9ra03423d · Cited by 70
Cullin Ring Ubiquitin Ligases (CRLs) in Cancer: Responses to Ionizing Radiation (IR) Treatment
Fouad, S., Wells, O. S., Hill, M. A., & D’Angiolella, V. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01144 · Cited by 67
Xia, L., Zheng, Z., Liu, J., Chen, Y.-J., Ding, J., Hu, G.-S., Hu, Y.-H., Liu, S., Luo, W., Xia, N., et al. (2021) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0405 · Cited by 65
The era of high-quality chemical probes
Licciardello, M. P., & Workman, P. (2022) · RSC Medicinal Chemistry · doi:10.1039/d2md00291d · Cited by 61
Wang, H., Yuan, S., Zheng, Q., Zhang, S., Zhang, Q., Ji, S., Wang, W. J., Cao, Y., Guo, Y., Yang, X., et al. (2024) · Gastroenterology · doi:10.1053/j.gastro.2024.01.025 · Cited by 67
Distinct Cdk9-phosphatase switches act at the beginning and end of elongation by RNA polymerase II
Parua, P. K., Kalan, S., Benjamin, B., Sansó, M., & Fisher, R. P. (2020) · Nature Communications · doi:10.1038/s41467-020-18173-6 · Cited by 65
Yang, L., Zhou, F., Zhuang, Y., Liu, Y., Xu, L., Zhao, H., Xiang, Y., Dai, X., Liu, Z., Huang, X., et al. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-01135-6 · Cited by 65
Coordinated regulation of RNA polymerase II pausing and elongation progression by PAF1
Wang, Z., Song, A., Xu, H., Hu, S., Tao, B., Peng, L., Wang, J., Li, J., Yu, J., Wang, L., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm5504 · Cited by 62
“To rule out the potential off-target effect of FP, we examined the impact on SPT5 phosphorylation by NVP-2, a highly selective P-TEFb inhibitor ( 70 ).”
BackgroundCossa, G., Röschert, I., Prinz, F., Baluapuri, A., Vidal, R. S., Schülein‐Völk, C., Chang, Y.-C., Ade, C. P., Mastrobuoni, G., Girard, C., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.008 · Cited by 65
“Comparison with published data describing the changes in RNAPII chromatin association in response to CDK9 inhibition (Olson et al., 2018) showed that although inhibition of CDK9 causes an accumulation of RNAPII at the pause site, the peaks 50 and 30 of the first exon-intron boundary were observed only in response to i…”
BackgroundFast-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 62
Self-citationAminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax
King, H. M., Rana, S., Kubica, S. P., Mallareddy, J. R., Kizhake, S., Ezell, E. L., Zahid, M., Naldrett, M. J., Alvarez, S., Law, H. C.-H., et al. (2021) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2021.128061 · Cited by 60
Xiao, L., Liu, Y., Chen, H., & Shen, L. (2023) · Cancer Biology & Therapy · doi:10.1080/15384047.2023.2219470 · Cited by 59
“The main effect of NVP-2 on CDK9 is to inhibit kinase activity and decrease the phosphorylation of Ser2 at CTD of RNAP II.(90,107) NVP-2 demonstrated greater suppression of BRAF/ NRAS/NF1 (BNF) cutaneous and uveal melanomas than mutant melanomas at 500 nM.”
BackgroundInfluentialG4-PROTAC: targeted degradation of a G-quadruplex binding protein
Patil, K. M., Chin, D., Seah, H. L., Shi, Q., Lim, K. W., & Phan, A. T. (2021) · Chemical Communications · doi:10.1039/d1cc05025g · Cited by 58
Wang, B., Wu, J., Wu, Y., Chen, C., Zou, F., Wang, A., Wu, H., Hu, Z., Jiang, Z., Liu, Q., et al. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.09.025 · Cited by 57
Yao, J., Xu, S. Q., Sun, Y., Xu, Y., Guo, Q., & Wei, L. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00708-2 · Cited by 56
Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation
Xi, M., Chen, Y., Yang, H., Xu, H., Du, K., Wu, C., Xu, Y., Deng, L., Luo, X., Yu, L., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.04.036 · Cited by 57
Discovery of First-In-Class Potent and Selective Tropomyosin Receptor Kinase Degraders
Chen, L., Chen, Y., Zhang, C., Jiao, B., Liang, S., Qiong, T., Chai, H., Yu, W., Qian, Y., Yang, H., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01342 · Cited by 55
Endres, T., Solvie, D., Heidelberger, J. B., Andrioletti, V., Baluapuri, A., Ade, C. P., Muhar, M., Eilers, U., Vos, S. M., Cramer, P., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2020.12.035 · Cited by 57
“If not specified otherwise inhibitor treatment of U2OS cells was as follows: Doxycycline (24h, 1 μg/ml), NVP-2 (3h, 1 μM), LDC4297 (0.5 μM, 3 h), BI8626 (10 μM, 4h), NMS-873 (5 μM, 4 h).”
BackgroundMethodInfluentialTargeting Protein Kinases Degradation by PROTACs
Yu, F., Cai, M., Shao, L., & Zhang, J. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.679120 · Cited by 55
“Surprisingly, it was found that the compound induced highly selective and rapid degradation of CDK9 without affecting the levels of other related targets (Olson et al., 2018).”
BackgroundDutta, R., Devarajan, A., Talluri, A., Das, R., & Thayumanavan, S. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c00131 · Cited by 56
Targeting cyclin-dependent kinase 9 in cancer therapy
Shen, Y., Wang, Y., Zhang, Y., Ma, S.-J., Yang, L., Zhao, C., & Huang, X. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00796-0 · Cited by 52
“This optimized compound exhibits higher selectivity for CDK9 in a cereblon (CRBN)-dependent fashion, and prolongs the inhibitory effect compared to traditional kinase inhibitors [130].”
BackgroundTherapeutic Targeting of the General RNA Polymerase II Transcription Machinery
Martin, R., Hébert, T. E., & Tanny, J. C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093354 · Cited by 51
Marak, B. N., Dowarah, J., Khiangte, L., & Singh, V. P. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112571 · Cited by 53
The mechanism of action and clinical value of PROTACs: A graphical review
Graham, H. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110446 · Cited by 56
“The CDK9 PROTAC was also shown to not affect other cellular processes that rely on the function of different CDK isoforms [13].”
BackgroundConfounding Factors in Targeted Degradation of Short-Lived Proteins
Vetma, V., Perez, L. C., Eliaš, J., Stingu, A., Kombara, A., Gmaschitz, T., Braun, N., Ciftci, T., Dahmann, G., Diers, E., et al. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00152 · Cited by 53
Ushering in the next generation of precision trials for pediatric cancer
DuBois, S. G., Corson, L., Stegmaier, K., & Janeway, K. A. (2019) · Science · doi:10.1126/science.aaw4153 · Cited by 53
Inhibition of O-GlcNAc Transferase Renders Prostate Cancer Cells Dependent on CDK9
Itkonen, H. M., Poulose, N., Steele, R. E., Martin, S. E. S., Levine, Z. G., Duveau, D. Y., Carelli, R., Singh, R., Urbanucci, A., Loda, M. F., et al. (2020) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0339 · Cited by 52
“NVP2 is a CDK9 inhibitor with >700-fold more selectivity for CDK9 than any other kinase (23).”
BackgroundResultInfluentialA critical evaluation of the approaches to targeted protein degradation for drug discovery
Chopra, R., Sadok, A., & Collins, I. (2019) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2019.02.002 · Cited by 53
“binders were converted into heterobifunctional degraders [34,35,36] and altered selectivity was also seen for a multi-”
BackgroundAdvancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence
Duran-Frigola, M., Cigler, M., & Winter, G. E. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c11098 · Cited by 50
Self-citationRational Design of Bioorthogonally Activatable PROTAC for Tumor-Targeted Protein Degradation
Bi, T., Pan, L., Zhou, Y., Wang, H., Huang, R., Sun, Q., Shen, H., Yang, S., Ren, W., & Liu, Z. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01423 · Cited by 52
Trapotsi, M.-A., Mouchet, E., Williams, G., Monteverde, T., Juhani, K., Turkki, R., Miljković, F., Martinsson, A., Mervin, L., Pryde, K. R., et al. (2022) · ACS Chemical Biology · doi:10.1021/acschembio.2c00076 · Cited by 51
“This makes it a pharmacologically interesting PROTAC because of its selective degradation of CDK9 with limited effects on the protein level of other CDKs (Olson et al., 2017).”
InfluentialHow many kinases are druggable? A review of our current understanding
Anderson, B. M., Rosston, P., Ong, H. W., Hossain, M. A., Davis‐Gilbert, Z. W., & Drewry, D. H. (2023) · Biochemical Journal · doi:10.1042/bcj20220217 · Cited by 49
Identifying transcriptional programs underlying cancer drug response with TraCe-seq
Chang, M. T., Shanahan, F., Nguyen, T. T. T., Staben, S. T., Gazzard, L. J., Yamazoe, S., Wertz, I. E., Piskol, R., Yang, Y. A., Modrusan, Z. D., et al. (2021) · Nature Biotechnology · doi:10.1038/s41587-021-01005-3 · Cited by 42
Riching, K. M., Schwinn, M. K., Vasta, J. D., Robers, M. B., Machleidt, T., Urh, M., & Daniels, D. L. (2020) · SLAS DISCOVERY · doi:10.1177/2472555220973602 · Cited by 46
Hati, S., Zallocchi, M., Hazlitt, R. A., Li, Y., Vijayakumar, S., Min, J., Ranković, Z., Lovas, S., & Zuo, J. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113849 · Cited by 46
Multi-therapies Based on PARP Inhibition: Potential Therapeutic Approaches for Cancer Treatment
Zhang, J., Gao, Y., Zhang, Z., Zhao, J., Jia, W., Xia, C., Wang, F., & Liu, T. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01352 · Cited by 49
Self-citationChoi, J., Bogenberger, J. M., & Tibes, R. (2020) · Targeted Oncology · doi:10.1007/s11523-020-00711-3 · Cited by 45
Bhurta, D., & Bharate, S. B. (2021) · Medicinal Research Reviews · doi:10.1002/med.21856 · Cited by 47
“It shows potent cytotoxicity in Molt‐4 cells (IC50 = 9 nM), but it is yet to be validated in the xenograft model.(292,293)”
BackgroundDevelopment of a PDEδ‐Targeting PROTACs that Impair Lipid Metabolism
Winzker, M., Friese, A., Koch, U., Janning, P., Ziegler, S., & Waldmann, H. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201913904 · Cited by 46
Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer
Ma, L., Li, Y., Luo, R., Wang, Y., Cao, J., Fu, W., Qian, B., Zheng, L., Tang, L., Lv, X., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00150 · Cited by 44
P-TEFb as A Promising Therapeutic Target
Fujinaga, K. (2020) · Molecules · doi:10.3390/molecules25040838 · Cited by 43
Řezníčková, E., Krajčovičová, S., Peřina, M., Kovalová, M., Soural, M., & Kryštof, V. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114792 · Cited by 43
PROTACS: A technology with a gold rush-like atmosphere
Wang, Y., Lan, L., Wang, M., Zhang, J., Gao, Y., Shi, L., & Sun, L. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.115037 · Cited by 44
The application of PROTAC in HDAC
Chen, S., Zheng, Y., Liang, B., Yin, Y., Yao, J., Wang, Q., Liu, Y., & Neamati, N. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115746 · Cited by 45
Zeng, Y., Xiao, J., Xu, Y., Fan, W., Tian, L., Gao, Y., Chen, Y., & Hu, Y. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00828 · Cited by 43
Induced proximity-based therapeutic modalities
King, E. A., Meyers, M., & Nomura, D. K. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01316-z · Cited by 61
“This has been robustly demonstrated in kinases: a pan-CDK binding ligand conjugated to thalidomide (THAL-SNS-032) induced CDK9-specific degradation, and dual CDK4 and CDK6 or CDK12 and CDK13 inhibitors were converted into isoform-specific CRBN-recruiting degraders 140–142 .”
Li, L., Xue, W., Shen, Z., Liu, J., Hu, M., Cheng, Z., Wang, Y., Chen, Y., Chang, H., Liu, Y., et al. (2020) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2020.06.013 · Cited by 41
“For example, Olson et al.(30) revealed that cyclin-dependent kinase 9 (CDK9) degradation can induce distinct pharmacological effects compared to its inhibition.”
BackgroundBéry, N., Keller, L., Soulié, M., Gence, R., Iscache, A.-L., Cherier, J., Cabantous, S., Sordet, O., Lajoie‐Mazenc, I., Pédelacq, J. D., et al. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.08.009 · Cited by 41
Identification and selectivity profiling of small-molecule degraders via multi-omics approaches
Scholes, N. S., Mayor‐Ruiz, C., & Winter, G. E. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.03.007 · Cited by 44
Self-citationRana, S., Mallareddy, J. R., Singh, S., Boghean, L., & Natarajan, A. (2021) · Cancers · doi:10.3390/cancers13215506 · Cited by 43
Cell-Based Ligand Discovery for the ENL YEATS Domain
Asiaban, J. N., Milosevich, N., Chen, E., Bishop, T. R., Wang, J. Q., Zhang, Y., Ackerman, C. J., Hampton, E. N., Young, T. S., Hull, M. V., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00124 · Cited by 37
Self-citationChemical Protein Degradation Approach and its Application to Epigenetic Targets
Itoh, Y. (2018) · The Chemical Record · doi:10.1002/tcr.201800032 · Cited by 41
Maneiro, M., Vita, E. D., Conole, D., Kounde, C. S., Zhang, Q., & Tate, E. W. (2021) · Progress in medicinal chemistry · doi:10.1016/bs.pmch.2021.01.002 · Cited by 38
Jorda, R., Havlíček, L., Peřina, M., Vojáčková, V., Pospíšil, T., Djukic, S., Škerlová, J., Grúz, J., Renešová, N., Klener, P., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c02184 · Cited by 39
London, N. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00570 · Cited by 37
CDK9 inhibitors in multiple myeloma: a review of progress and perspectives
Borowczak, J., Szczerbowski, K., Ahmadi, N., & Szylberg, Ł. (2022) · Medical Oncology · doi:10.1007/s12032-021-01636-1 · Cited by 38
“THAL-SNS-032 and PROTAC B03 induced rapid degradation of CDK9 without affecting the levels of other CDKs [94, 97].”
BackgroundInfluentialCollateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities
Zhang, Y., Remillard, D., Onubogu, U., Karakyriakou, B., Asiaban, J. N., Ramos, A. R., Bowland, K., Bishop, T. R., Barta, P. A., Nance, S., et al. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01041-4 · Cited by 35
Self-citationSelective Kinase Inhibition Shows That Bur1 (Cdk9) Phosphorylates the Rpb1 Linker In Vivo
Chun, Y., Suh, H., Joo, Y. J., Batot, G., Hill, C. P., Formosa, T., & Buratowski, S. (2019) · Molecular and Cellular Biology · doi:10.1128/mcb.00602-18 · Cited by 36
“Chemical inhibitors are available that target the native mammalian kinases with varying levels of specificity (21-23).”
BackgroundA PROTAC targets splicing factor 3B1
Gama-Brambila, R. A., Chen, J., Zhou, J., Tascher, G., Münch, C., & Cheng, X. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.018 · Cited by 37
Targeted Protein Degradation: Design Considerations for PROTAC Development
Tran, N. L., Leconte, G. A., & Ferguson, F. M. (2022) · Current Protocols · doi:10.1002/cpz1.611 · Cited by 35
Wu, T., Zhang, Z., Gong, G., Xu, Y., Xu, Y., Yu, S., Ma, F., Zhang, X., Wang, Y., Chen, H., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115774 · Cited by 35
Self-citationWang, Y., Chen, X., Yan, Y., Zhu, X., Liu, M., & Liu, X. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02121 · Cited by 35
Selectively targeting individual bromodomain: Drug discovery and molecular mechanisms
Wang, Q., Shao, X., Leung, E. L., Chen, Y., & Yao, X. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105804 · Cited by 34
Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia
Han, X., Song, N., Saidahmatov, A., Wang, P., Wang, Y., Hu, X., Kan, W., Zhu, W., Gao, L., Zeng, M., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01148 · Cited by 35
Transcriptional cyclin-dependent kinases: Potential drug targets in cancer therapy
Liu, Y., Fu, L., Wu, J., Liu, M., Wang, G., Liu, B., & Zhang, L. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.114056 · Cited by 38
Metadata
- 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
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
