Abstract B164: Identification of a novel highly selective and orally bioavailable preclinical candidate for CDK7 covalent inhibition
Authors: Poddutoori Ramulu , Khare Satyam Leena , Mukherjee Subhendu , Marappan Sivapriya , Gopinath Sreevalsam , KB Charamanna , Kaza Lakshmi Narayana , Pothuganti Manoj Kumar , Rajagopalan Sujatha , Sivakumar Sasirekha , E N Bharath , A B Aravind , A Amith , M V Ravindra , Tgore Suraj , Antony Thomas , Pandit Chetan , Chelur Shekar , Daginakatte Girish , Ramachandra Murali , Samajdar Susanta 
Published: August 2018

Abstract
Background: Cyclin-dependent kinase 7 (CDK7) is an important constituent of the cellular transcriptional machinery, where it phosphorylates the C-terminal domain (CTD) of RNAP polymerase II (RNAPII). Because many tumor types are critically dependent on transcription for maintenance of their oncogenic state, pharmacologic modulation of CDK7 kinase activity is considered as an approach to treat cancer. Experimental Procedures: Multiple series of covalent CDK7 inhibitors were identified by iterative medicinal chemistry efforts and SAR-based approach. These compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity, and desirable pharmacokinetic profile to achieve antitumor activity. Summary: We have now identified a highly selective and orally bioavailable covalent CDK7 inhibitor AU-002 as a preclinical candidate. AU-002 is highly potent in inhibiting CDK7 in biochemical assays with robust engagement of CDK7 in cellular context. In a broad panel of 372 kinases, AU-002 shows excellent selectivity for CDK7. AU-002 exhibits excellent drug-like characteristics including solubility, permeability, metabolic stability, and good oral bioavailability. Oral treatment of this compound in a xenograft model resulted in dose-dependent tumor growth inhibition in AML xenograft model and with complete tumor regression at well-tolerated doses. Potent inhibition of tumor growth was accompanied by complete target engagement and suppression of pS5RNAPII in a parallel PK-PD study. Efficacy studies in additional xenograft models, advanced DMPK, and toxicity studies are ongoing for this compound. Conclusion: We have identified a novel and highly selective CDK7 covalent inhibitor candidate with good oral bioavailability that shows excellent efficacy in an AML xenograft model. Findings presented here support further development of AU-002 for the treatment of cancer.
Citation Format: Ramulu Poddutoori, Leena Khare Satyam, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Charamanna KB, Lakshmi Narayana Kaza, Manoj Kumar Pothuganti, Sujatha Rajagopalan, Sasirekha Sivakumar, Bharath E N, Aravind A B, Amith A, Ravindra M V, Suraj Tgore, Thomas Antony, Chetan Pandit, Shekar Chelur, Girish Daginakatte, Murali Ramachandra, Susanta Samajdar. Identification of a novel highly selective and orally bioavailable preclinical candidate for CDK7 covalent inhibition [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 B164.