Abstract A174: Novel inhibitors of protein arginine methyltransferase 5 (PRMT5) for the treatment of solid tumors
Authors: Chikkanna Dinesh , Panigrahi Sunil Kumar , Rajagopalan Sujatha , Sammeta Srinivasa Raju , Lakshminarasimhan Anirudha , R Mohan , K Narasihmarao , Chawla Darshan , Bhat Harsha , Kasturi Venkateswarlu , D.S Samiulla , Prasanna Angelene , Aithal Kiran , Chand Priyabrata Chand , Kumar Naveen , Marri Sai Sudheer , Ganipisetty Srinivasa Rao , N Kasieswara Rao , Mutyala Raju , Neerukattu Nageswara Rao , K Nithesh , Amin Ramya , Gorade Priyanka Machhindra , Antony Thomas , Daginakatte Girish , Chelur Shekar , Pandit Chetan , Samajdar Susanta , Ramachandra Murali 
Published: August 2018

PRMT5 is a typical type II methyltransferase, transferring two methyl groups to arginine, leading to symmetric dimethylation of the substrate. It can symmetrically methylate histones H2AR3, H3R2, H3R8, and H4R3 and can also methylate many non-histone proteins contributing to tumorigenesis by regulating cell cycle progression, DNA repair, cell growth, apoptosis, and inflammation. Overexpression of PRMT5 is reported in several human malignancies including lymphoma, glioma, melanoma, lung, breast, ovarian, and prostate cancers. Elevated levels correlate with poor prognosis in NSCLC, ovarian cancers, and GBM. Therefore, PRMT5 is considered an attractive target for cancer therapy. We sought to discover and develop PRMT5 inhibitors with the “best-in-class” profile with an emphasis on improved brain permeability for their potential use in solid tumors including glioblastoma. Utilizing structure-guided drug design and SAR-based approaches, we have optimized two chemical series of substrate competitive PRMT5 inhibitors. Determination of co-crystal structures with several de novo designed hits aided in the identification of lead compounds that exhibited potent inhibition of PRMT5. Lead compounds were highly active in inhibiting proliferation of a number of cell lines derived from solid tumors that correlated well with cellular H4R3Me2s inhibition, confirming the mechanism. Lead compounds exhibited desirable drug-like properties including solubility, permeability, lack of CYP inhibition, and pharmacokinetic exposure. A substantial improvement in brain permeability over reported PRMT5 inhibitors was noted in rodent pharmacokinetic studies. In a xenograft model of lung cancer, treatment with lead compounds resulted in significant tumor growth inhibition while correlating with tumor drug levels and modulation of H4R3Me2s as the pharmacodynamic effect. In summary, we have identified PRMT5 inhibitors with “best-in-class" drug-like properties including optimized brain permeability and antitumor efficacy. Evaluation of the efficacy of these lead compounds in additional xenograft models including glioblastoma is currently under way.

Citation Format: Dinesh Chikkanna, Sunil Kumar Panigrahi, Sujatha Rajagopalan, Srinivasa Raju Sammeta, Anirudha Lakshminarasimhan, Mohan R, Narasihmarao K, Darshan Chawla, Harsha Bhat, Venkateswarlu Kasturi, Samiulla D.S, Angelene Prasanna, Kiran Aithal, Priyabrata Chand Chand, Naveen Kumar, Sai Sudheer Marri, Srinivasa Rao Ganipisetty, Kasieswara Rao N, Raju Mutyala, Nageswara Rao Neerukattu, Nithesh K, Ramya Amin, Priyanka Machhindra Gorade, Thomas Antony, Girish Daginakatte, Shekar Chelur, Chetan Pandit, Susanta Samajdar, Murali Ramachandra. Novel inhibitors of protein arginine methyltransferase 5 (PRMT5) for the treatment of solid tumors [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 A174.