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Ref Type Journal Article
PMID (30454645)
Authors Zhang H, Pandey S, Travers M, Sun H, Morton G, Madzo J, Chung W, Khowsathit J, Perez-Leal O, Barrero CA, Merali C, Okamoto Y, Sato T, Pan J, Garriga J, Bhanu NV, Simithy J, Patel B, Huang J, Raynal NJ, Garcia BA, Jacobson MA, Kadoch C, Merali S, Zhang Y, Childers W, Abou-Gharbia M, Karanicolas J, Baylin SB, Zahnow CA, Jelinek J, Graña X, Issa JJ
Title Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer.
Journal Cell
Vol 175
Issue 5
Date 2018 Nov 15
URL
Abstract Text Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MC180295 MC180295 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MC180295 CDK9 Inhibitor 16 MC180295 selectively inhibits CDK9, resulting in increased expression of silenced genes, and potentially leading to decreased proliferation and increased differentiation of tumor cells (PMID: 30454645).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown breast cancer not applicable MC180295 Preclinical - Cell culture Actionable In a preclinical study, MC180295 decreased proliferation of a breast cancer cell line in culture (PMID: 30454645). 30454645
Unknown unknown prostate cancer not applicable MC180295 Preclinical - Cell culture Actionable In a preclinical study, MC180295 decreased proliferation of prostate cancer cell lines in culture (PMID: 30454645). 30454645
Unknown unknown leukemia not applicable MC180295 Preclinical - Cell culture Actionable In a preclinical study, MC180295 decreased proliferation and increased differentiation of leukemia cells in culture (PMID: 30454645). 30454645
Unknown unknown ovarian cancer not applicable SNS-032 Preclinical Actionable In a preclinical study, SNS-032 decreased tumor burden and increased survival in a syngeneic mouse ovarian cancer model (PMID: 30454645). 30454645
Unknown unknown colon cancer not applicable MC180295 Preclinical - Cell line xenograft Actionable In a preclinical study, MC180295 decreased growth of colon cancer cell lines in culture, and reduced tumor growth rate and improved survival in colon cancer cell line xenograft models (PMID: 30454645). 30454645
Unknown unknown ovarian cancer not applicable SNS-032 + unspecified PD-1 antibody Preclinical Actionable In a preclinical study, the addition of SNS-032 resulted in sensitization to anti-PD-1 therapy in a syngeneic mouse ovarian cancer model, resulting in increased immune response and decreased tumor burden (PMID: 30454645). 30454645