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|Ref Type||Journal Article|
|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.|
|Date||2018 Nov 15|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|