ArticleActa pharmaceutica Sinica. B2023
Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy.
Article in Acta pharmaceutica Sinica. B, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- miR-640 Enhances Abemaciclib Sensitivity by Suppressing CDK Inhibitor Resistance-Associated Genes in Breast Cancer Cells.Journal of cellular and molecular medicine · 2026Article
- A potent and selective PROTAC degrader of CDK9 as effective inhibitor of HIV-1 RNA synthesis.Molecular diversity · 2026Article
- CDK9 and hematologic malignancies: pioneering novel therapeutic approaches.Clinical and experimental medicine · 2026Review
- Pharmacological inhibition of PGK1 suppresses EGFR-positive esophageal squamous cell carcinoma by dual targeting of glycolysis and autophagy-dependent EGFR degradation.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Article
- CDK9 degrader induces BRCAness and sensitizes castration-resistant prostate cancer to PARP inhibitor.Theranostics · 2026Article
- Introduction to Cancer Metabolism.Cancer treatment and research · 2026Review
- A functional map of CDK-drug interactions at single amino acid resolution.bioRxiv : the preprint server for biology · 2025Article
- Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review.Journal of Zhejiang University. Science. B · 2025Review
- Enhancer regulation in cancer: from epigenetics to mArchives of pharmacal research · 2025Review
- First ATG101-recruiting small molecule degrader for selective CDK9 degradationActa pharmaceutica Sinica. B · 2025Article
- Safety and Efficacy of a Selective Inhibitor of Cyclin-dependent Kinase 9 (KB-0742) in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma.Cancer research communications · 2025Article
- Targeting METTL3 mitigates venetoclax resistance via proteasome-mediated modulation of MCL1 in acute myeloid leukemia.Cell death & disease · 2025Article
- CDK9 inhibitors for the treatment of solid tumors.Biochemical pharmacology · 2024Review
- Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets.Molecular cancer · 2024Review
- Pyrazine-based small molecule kinase inhibitors: clinical applications and patent review (2019-2023).Future medicinal chemistry · 2024Review
- Overcoming drug resistance through extracellular vesicle-based drug delivery system in cancer treatment.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Cancer therapy by cyclin-dependent kinase inhibitors (CDKIs): bench to bedside.EXCLI journal · 2024Review
- The involvement of cyclin-dependent kinase 7 (CDK7) and 9 (CDK9) in coordinating transcription and cell cycle checkpoint regulation.Cell cycle (Georgetown, Tex.)Review
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival. Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers. However, the study and knowledge on drug resistance to CDK9 inhibitors are very limited. In this study, we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152. Through genomic sequencing, we identified in the kinase domain of CDK9 a mutation L156F, which is also a coding SNP in the CDK9 gene. By knocking in L156F into cancer cells using CRISPR/Cas9, we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors, not only ATP competitive inhibitor but also PROTAC degrader. Mechanistically, CDK9 L156F disrupts the binding with inhibitors due to steric hindrance, further, the mutation affects the thermal stability and catalytic activity of CDK9 protein. To overcome the drug resistance mediated by the CDK9-L156F mutation, we discovered a compound, IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant. Together, we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.
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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.