Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors

Yang Gao, Tinghu Zhang, Hideki Terai, Scott B. Ficarro, Nicholas Kwiatkowski, Ming Feng Hao, Bandana Sharma, Camilla L. Christensen, Edmond Chipumuro, Kwok kin Wong, Jarrod A. Marto, Peter S. Hammerman, Nathanael S. Gray, Rani E. George

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)


Irreversible inhibition of transcriptional cyclin-dependent kinases (CDKs) provides a therapeutic strategy for cancers that rely on aberrant transcription; however, lack of understanding of resistance mechanisms to these agents will likely impede their clinical evolution. Here, we demonstrate upregulation of multidrug transporters ABCB1 and ABCG2 as a major mode of resistance to THZ1, a covalent inhibitor of CDKs 7, 12, and 13 in neuroblastoma and lung cancer. To counter this obstacle, we developed a CDK inhibitor, E9, that is not a substrate for ABC transporters, and by selecting for resistance, determined that it exerts its cytotoxic effects through covalent modification of cysteine 1039 of CDK12. These results highlight the importance of considering this common mode of resistance in the development of clinical analogs of THZ1, identify a covalent CDK12 inhibitor that is not susceptible to ABC transporter-mediated drug efflux, and demonstrate that target deconvolution can be accomplished through selection for resistance. Gao et al. report ABC transporter upregulation as a major mechanism of acquired resistance to the THZ series of covalent CDK7/12/13 inhibitors and describe the generation of E9, which escapes drug efflux and whose target selectivity was confirmed by the acquisition of a CDK12-binding site mutation in E9-resistant cells.

Original languageEnglish
Pages (from-to)135-142.e5
JournalCell Chemical Biology
Issue number2
Publication statusPublished - 2018 Feb 15
Externally publishedYes


  • covalent transcriptional CDK inhibitor
  • drug resistance
  • pediatric and adult solid tumors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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