Cancer

Cell culture and mouse studies identified a CDK7/CDK12/CDK13 inhibitor that could help treat ovarian cancer. Screening of 42 small molecules targeting transcriptional and/or epigenetic components in two human ovarian cancer cell lines identified a CDK7/CDK12/CDK13 inhibitor tool compound that inhibited growth with EC₅₀ values of about 0.1 and 0.2 μM. Also in the cell lines, the combination of a CDK7 inhibitor and CDK12/CDK13 inhibitor recapitulated the reductions in CDK-dependent expression of v-myc myelocytomatosis viral oncogene homolog (MYC; c-Myc) and myeloid leukemia cell differentiation protein (MCL1) observed for the triple inhibitor, whereas the CDK7 inhibitor or CDK12/CDK13 inhibitor alone did not. In 11 orthotopic patient-derived xenograft (PDX) mouse models of ovarian cancer, the compound decreased tumor growth compared with vehicle or Lynparza olaparib. In five of the models, the compound plus Lynparza decreased tumor growth compared with the compound alone. Next steps could include optimizing and testing the compound in the PDX models...