ArticleCell chemical biology2018
Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors.
Article in Cell chemical biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
42 citing papers in PubMed, 76 citations in OpenAlex.
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- Pan-cancer multi-omics characterization of CDK12 and virtual screening of Vietnamese natural products for novel inhibitors.Molecular diversity · 2026Article
- Recent advances in development of CDK7 inhibitors and their clinical trials: a narrative review.Translational cancer research · 2025Review
- High-throughput profiling of chemical-induced gene expression across 93,644 perturbations.Nature methods · 2025Article
- New insights into the dule roles CDK12 in human cancers: Mechanisms and interventions for cancer therapy.Journal of pharmaceutical analysis · 2025Review
- Novel Small Molecule Inhibitors of Cyclin-dependent Kinases as Anticancer Agents.Current medicinal chemistry · 2025Review
- Development of CDK12 as a Cancer Therapeutic Target and Related Inhibitors.Current cancer drug targets · 2025Review
- Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7).European journal of medicinal chemistry · 2024Article
- Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets.Molecular cancer · 2024Review
- Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier.Fluids and barriers of the CNS · 2024Article
- Research progress of anticancer drugs targeting CDK12.RSC medicinal chemistry · 2023Review
- Systematic screening identifies ABCG2 as critical factor underlying synergy of kinase inhibitors with transcriptional CDK inhibitors.Breast cancer research : BCR · 2023Article
- Identification and Empiric Evaluation of New Inhibitors of the Multidrug Transporter P-Glycoprotein (ABCB1).International journal of molecular sciences · 2023Article
- Superenhancers as master gene regulators and novel therapeutic targets in brain tumors.Experimental & molecular medicine · 2023Review
- Modulating Glycolysis to Improve Cancer Therapy.International journal of molecular sciences · 2023Review
- Targeting pre-mRNA splicing in cancers: roles, inhibitors, and therapeutic opportunities.Frontiers in oncology · 2023Review
- Article
- Review
- Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Response and resistance to CDK12 inhibition in aggressive B-cell lymphomas.Haematologica · 2022Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.