Abstract 5221: Development of TGN-1076, a selective and reversible small molecule inhibitor of CDK7

Purpose: Tumor genetic heterogeneity can lead to dysregulation of transcriptional programs and cause cancer cells to become highly dependent on certain regulators of gene expression. Super-enhancers (SEs) are a class of regulatory regions that are associated with a strong enrichment of transcriptional coactivators (MED1, BRD4) and chromatin marks (H3K27Ac). It has been shown that tumor cells can acquire SEs at oncogenic driver genes (MYC, TERT, BCL2, GFI1, MED1, OCT4, and SOX2), activate their expression, and induce transcriptional reprogramming. Importantly, the majority of super-enhancers depend on the ability of cyclin-dependent kinase 7 (CDK7) to initiate transcription by phosphorylating the C-terminal domain of RNA Pol II. Recent reports have shown that high level of CDK7 is associated with poor prognosis in breast, gastric, ovarian, pancreatic, SCLC, ATC, and AML cancers. We have embarked on developing a novel therapeutic that specifically targets the CDK7 catalytic ATP pocket. Previously, we reported the discovery of TGN-1062 as a potent inhibitor of CDK7. In this study, we report the development of TGN-1076, an analog of TGN-1062, as a selective and reversible inhibitor of CDK7 due to its ideal candidate criteria. Methods: With structure-guided and iterative medicinal chemistry approaches, the previous lead candidate TGN-1062 was further optimized to improve potency, target selectivity, and desirable drug-like properties. In vitro kinase assays were performed using ADP-GloTM kinase assay kit (Promega). Cell viability assays were performed in a panel of cancer cell lines using CellTiter-Glo assay kit (Promega). RNA Pol II phosphorylation and total MYC protein levels were determined by Western Blotting. Results: TGN-1076 inhibited CDK7 activity with an IC50 of 20 nM and showed 10-500 fold selectivity against the closest members of the CDK family. TGN-1076 blocked growth of multiple cancer cells, among these pancreatic cancer cells were most sensitive with an GI50 of