Abstract B165: Potent selective and orally bioavailable inhibition of CDK12 by novel covalent inhibitors
Authors: Poddutoori Ramulu , Rajagopalan Sujatha , Mukherjee Subhendu , Marappan Sivapriya , D S Samiulla , Kasturi Venkateswarlu , Sivakumar Sasirekha , Nayak Shilpa , M V Ravindra , Tgore Suraj , Dhudashiya Amit , K B Charamanna , Antony Thomas , M Mahaboobi , Giri Sanjeev , Daginakatte Girish C. , Chelur Shekar , Ramachandra Murali , Pandit Chetan , Samajdar Susanta 
Published: August 2018

Abstract
Background: Cyclin-dependent kinase 12 (CDK12) coordinately regulates the transcription, splicing, and alternative splicing of several large pre-mRNAs. Defective CDK12 kinase activity has been associated with genomic instability and downregulation of genes in the DNA damage response (DDR) pathway. In addition, CDK12 depletion impairs alternate splicing, a process being increasingly implicated in cancer progression. Associated with Cyclin K (CycK), CDK12 regulates transcription elongation by phosphorylating RNA polymerase II (RNAP II) at S2 in the C-terminal domain (CTD). Considering its role in transcription and RNA processing to maintain genomic stability/integrity in cancer, CDK12 is emerging as a potential therapeutic target to treat cancer. Experimental Procedures: Potent and selective CDK12 inhibitors were identified from multiple series by iterative medicinal chemistry efforts and SAR-based approaches. Early compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity, and desirable pharmacokinetic profile to achieve antitumor activity.Summary: Very potent and highly selective compounds were identified from two distinct chemical series that are highly potent in inhibiting CDK12 in biochemical assays. Proving their covalent mode of action, these orally exposed compounds demonstrated robust engagement of CDK12 in a cellular context. Several of these potent and selective CDK12 inhibitors showed potent antiproliferative activity in various cancer cell lines derived from different origin, accompanied by robust CDK12 engagement and inhibition of pS2 (RNAP II). Further optimization of potency and ADME properties of initial lead compounds is in progress. Tolerability and efficacy studies are ongoing with selected early leads to test their impact on tumor growth inhibition in xenograft models. Conclusion: We identified novel, selective, and orally bioavailable covalent inhibitors of CDK12 from multiple distinct series with desirable drug-like properties, which are being evaluated for antitumor activity in xenograft models.
Citation Format: Ramulu Poddutoori, Sujatha Rajagopalan, Subhendu Mukherjee, Sivapriya Marappan, Samiulla D S, Venkateswarlu Kasturi, Sasirekha Sivakumar, Shilpa Nayak, Ravindra M V, Suraj Tgore, Amit Dhudashiya, Charamanna K B, Thomas Antony, Mahaboobi M, Sanjeev Giri, Girish C. Daginakatte, Shekar Chelur, Murali Ramachandra, Chetan Pandit, Susanta Samajdar. Potent selective and orally bioavailable inhibition of CDK12 by novel covalent inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B165.