Abstract 48P
Background
Cyclin-dependent kinase 7 (CDK7) has emerged as an exciting target for oncotherapy because it controls both the cell cycle and RNA Pol II-mediated transcription, two critical processes dysregulated in cancer cells. Here, we report the discovery of a novel, orally bioavailable CDK7 early lead inhibitor (BWC 5044) identified through structure-guided drug design. BWC5044 has shown promising results in preclinical efficacy studies, with enhanced anti-tumour activity and improved overall survival rates. Furthermore, in combination with FDA-approved drugs, the lead compounds showed a significantly synergistic effect by enhancing tumour killing in patient derived ex vivo and pre-clinical setting.
Methods
The antitumor activity of BWC5044, an orally bioavailable CDK7 inhibitor, was investigated using different cancer models in vitro and in vivo. Cell-based assays and cell signalling analyses of treated cells in situ and ex vivo were employed to investigate the mechanisms driving BWC5044 activity, alone and in combination with approved FDA drugs.
Results
BWC5044 selectively engages with CDK7 in an in situ NanoBRET assay, causing inhibition of proliferation and cell cycle arrest. At the molecular level, treatment of cancer cells with a sub-cytotoxic concentration of BWC5044 downregulated RNA Pol II phosphorylation. We also observed downregulation of c-Myc and several proliferation markers. We have optimised the early lead series by using structure-based design and obtained highly selective leads for CDK7, which are more potent than investigational CDK7 inhibitors under clinical development. Based on ex-vivo test results, we prioritized the top synergistic combinations and tested them in vivo, finding that drugs A and B displayed effective synergy.
Conclusions
CDK7 is a key regulator of cell cycle progression, and its inhibition has shown promising results in targeting abnormal cell growth. The rational combination of BWC5044 with selected FDA-approved drugs has been found to be synergistic in reducing tumour burden. This multi-modal treatment approach holds great promise for improving outcomes in various cancer types, making BWC5044 a promising candidate for a breakthrough medication.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Bugworks Research India Private Ltd.
Funding
Bugworks Research India Private Ltd.
Disclosure
S. Setua, N. Belugali Nataraj, R. Rao, S. Venkatesan, S. Sarma, P. Bhowmik, S. Suresh, H. Kaushik Kotakonda, S. Reddy, M. Gupta, N. Katagihallimath: Financial Interests, Personal, Stocks/Shares: Bugworks Research India Pvt Ltd. S. Datta: Financial Interests, Personal, Advisory Role: Bugworks Research India Pvt Ltd.; Financial Interests, Personal, Stocks/Shares: Bugworks Research India Pvt. S. Hameed P: Financial Interests, Personal, Stocks/Shares: Bugworks Research India Pvt Ltd.; Financial Interests, Personal, Other, Chief Scientific Officer: Bugworks Research India Pvt. All other authors have declared no conflicts of interest.