Abstract 1392: Preclinical In vivo evaluation of efficacy, pharmacokinetics and pharmacodynamics of novel PRMT5 inhibitors in multiple tumor models
Authors: Chikkanna Dinesh , Panigrahi Sunil Kumar , Rajagopalan Sujatha , Sammeta Srinivasa Raju , Chawla Darshan , S Pavithra , D.S Samiulla , Prasanna Angelene , Chand Priyabrata , Aithal Kiran , Marri Sai Sudheer , Kumar Naveen , Ganipisetty Srinivasa Rao , Mutyala Raju , Rao Kasieswara , Antony Thomas , Daginakatte Girish , Lakshminarasimhan Anirudha , R Mohan , K Narasihmarao , 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 permeability for their potential use in solid tumors. 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 AU-574 and AU-755 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. In xenograft models of Z-138 (lymphoma) and H-358 (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 permeability and antitumor efficacy. Evaluation of these lead compounds in in vitro selectivity screening and in toxicity studies in higher species is currently under way.

Citation Format: Dinesh Chikkanna, Sunil Kumar Panigrahi, Sujatha Rajagopalan, Srinivasa Raju Sammeta, Darshan Chawla, Pavithra S, Samiulla D.S, Angelene Prasanna, Priyabrata Chand, Kiran Aithal, Sai Sudheer Marri, Naveen Kumar, Srinivasa Rao Ganipisetty, Raju Mutyala, Kasieswara Rao, Thomas Antony, Girish Daginakatte, Anirudha Lakshminarasimhan, Mohan R, Narasihmarao K, Shekar Chelur, Chetan Pandit, Susanta Samajdar, Murali Ramachandra. Preclinical In vivo evaluation of efficacy, pharmacokinetics and pharmacodynamics of novel PRMT5 inhibitors in multiple tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1392.