Abstract 339: Identification of novel covalent inhibitors of K-Ras G12C that are efficacious in a xenograft model of NSCLC

Abstract

KRAS is the frequently mutated isoform in RAS driven cancers. The G12C mutation is more predominantly associated with various tumor types over other changes in K-Ras. Although direct targeting of RAS is very challenging, it is possible to selectively target G12C mutant K-Ras using a covalent approach. Mutant specific covalent inhibitors with high selectivity against wild type K-Ras and other GTPases are expected to lead to efficacy with a very high degree of tolerability. Here, we report identification of lead compounds from two distinct chemical series that selectively target K-Ras G12C. Molecular modeling based on the reported crystal structures aided in the identification of these compounds. Covalent binding of the lead compounds to K-Ras G12C was demonstrated by MALDI-TOF. Lead compounds were potent in selectively inhibiting proliferation of cell lines with K-Ras G12C mutation but not with wild type K-Ras. The anti-proliferative activity of the lead compounds correlated well with their potency in a cellular mechanistic assay. Lead compounds from both series exhibited excellent drug-like properties including solubility, metabolic stability, permeability lack of CYP inhibition and desired exposure in pharmacokinetic studies. In a xenograft model of NSCLC, the lead compound demonstrated dose-dependent tumor growth inhibition with excellent tolerability upon oral dosing. In summary, we have identified a novel, potent and selective K-Ras G12C inhibitor with optimized drug-like properties including oral bioavailability and efficacy in a NSCLC derived xenograft model. Toxicity evaluation is ongoing towards progressing the lead compound to the clinic. Citation Format: Leena Khare Satyam, Dinesh Chikkanna, Aswani K. G, Vinayak V. Khairnar, Sreekanth Reddy, Vakkapatla Durgaprasad, Kowju Radhakrishna, Sunil K. Panigrahi, Anuradha Ramanathan, Kumari Mahasweta, Anirudha Lakshminarasimhan, Narasimha R. K, Vinutha R, Sreevalsam Gopinath, Suryakant Kumar, Mubarak H. Shah, Raghuveer Ramachandra, Kiran A. B, Chetan Pandit, Murali Ramachandra. Identification of novel covalent inhibitors of K-Ras G12C that are efficacious in a xenograft model of NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 339.

The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D

“…[301][302][303] Additionally,t he companies are also exploring selectiveB ET inhibitors. Other projects continue internally with as trong focus on oncology,i ncluding with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors such as AU-4869, [304] covalentK -Ras inhibitors, [305] or CDK7 inhibitors, [306] and RAR-related orphan receptor g (RORg)i nverse agonists for the treatment of inflammatoryd isorders. [307] Additional approaches targeted the treatment of infections with PD-1 inhibitors, [293] or with FabI (enoyl-acyl carrierp rotein (ACP) reductase)i nhibitors such as AEA16 34.…”