Sy-1365, A Potent And Selective Cdk7 Inhibitor, Exhibits Promising Anti-Tumor Activity In Multiple Preclinical Models Of Aggressive Solid Tumors

CDK7 has recently emerged as an attractive target in cancer since its inhibition decreases the transcript levels of oncogenic transcription factors, especially those driven by super-enhancers (SEs). Cancers have been hypothesized to be addicted to SE regulated genes and simultaneous suppression of multiple SE associated genes through CDK7 inhibition might represent a novel, powerful way to selectively kill cancer cells. Previously, we reported that SY-1365, a highly selective covalent CDK7 inhibitor, induces apoptosis in leukemia cells, but not in non-malignant cells, and demonstrates anti-tumor activity in in vivo models of leukemia. In this study, we extend these findings to the identification of multiple solid tumors that are susceptible to SY-1365 and compare the effects of SY-1365 on gene expression to other gene control agents. SY-1365 was screened in a panel of solid tumor cell lines, revealing activity in breast, ovarian, colorectal and lung cancer cells with low nM EC 50 and rapid induction of apoptosis. In breast cancer, a subset of triple negative breast cancer (TNBC) cell lines were found to be more sensitive than luminal breast cancer cell lines, so we extended our studies to in vivo models and showed substantial tumor growth inhibition in multiple patient-derived xenograft (PDX) models of TNBC. Since other compounds have been reported to modulate the expression of SE regulated genes, we compared the transcriptional effects of SY-1365 treatment with those of a pan-CDK inhibitor (flavopiridol), a CDK9 inhibitor (NVP2) and a BRD4 inhibitor (JQ1) using microarray analysis. Applying principal component analysis, we observed a unique transcriptional response elicited by SY-1365 compared to the other inhibitors. NVP2 and flavopiridol inhibited an overlapping and much larger gene set than either JQ1 or SY-1365. Interestingly, SY-1365 treatment decreased the expression of oncogenic transcription factors, cell cycle checkpoint regulators and DNA damage response genes. The downregulation of transcripts involved in apoptosis and DNA damage response by SY-1365 suggests that CDK7 inhibition might synergize with targeted agents that affect these processes. Indeed, we observed that SY-1365 was synergistic with the PARP inhibitor niraparib and the Bcl-2 inhibitor venetoclax in triple negative breast cancer and AML cell lines, respectively. In summary, we have identified TNBC, ovarian and small cell lung cancer cell lines as highly sensitive to SY-1365 in vitro and have observed substantial tumor growth inhibition in PDX models of TNBC. SY-1365 induced a distinct transcriptional response compared with other transcriptional inhibitors, with apoptotic and DNA damage pathways being central. Finally, these mechanism of action studies support a rationale for investigating combinations of SY-1365 with inhibitors of PARP and Bcl-2. Citation Format: Shanhu Hu, Nan Ke, Yixuan Ren, Sofija Miljovska, Nisha Rajagopal, Michael McKeown, David Orlando, Kevin Sprott, Yoon J. Choi, Eric Olson, Christian C. Fritz. SY-1365, a potent and selective CDK7 inhibitor, exhibits promising anti-tumor activity in multiple preclinical models of aggressive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1151. doi:10.1158/1538-7445.AM2017-1151