Abstract 5367: Discovery of dihydro-isoxazole derivatives as novel inhibitors of NAMPT for the treatment of multiple myeloma

Abstract

Abstract Nicotinamide phosphoribosyl transferase (NAMPT) is the enzyme that catalyzes the rate-limiting step in the salvage pathway of Nicotinamide Adenine Dinucleotide (NAD) biosynthesis. NAMPT is overexpressed in a number of cancers, and inhibition of NAMPT has been shown to result in anti-tumor efficacy in preclinical models. Clinical development to first generation NAMPT inhibitors has been hindered because of their poor pharmacological profile, high cytochrome inhibition and possibly mechanism-based toxicities. Therefore, we sought to develop NAMPT inhibitors with the “best-in-class” profile for overcoming mechanism-based toxicities and/or resistance to current therapies. Utilizing structure-guided drug design including determination of co-crystal structures and SAR-based approaches, we have identified a novel chemical series of inhibitors of NAMPT. Optimization of the series for transient target inhibition as a result of reduced binding strength coupled with desirable pharmacokinetic profile to minimize mechanism based toxicity resulted in identification of AU-4869 as the Lead compound.AU-4869 showed potent cross-species activity and reduced strength of binding in comparison with first generation NAMPT inhibitors. Anti-proliferative activity of AU-4869 correlated well with NAD depletion in multiple cell lines derived from multiple myeloma and Pancreatic cancers. The anti-proliferative activities were rescued in NAPRT-proficient cell lines with the addition of NA due to the NAMPT independent salvage pathway for biosynthesis of NAD, confirming the mechanism of action through NAD depletion. AU-4869 exhibited desirable drug-like properties including solubility, permeability, metabolic stability, lack of CYP & hERG inhibition and pharmacokinetic exposure upon oral dosing. At well-tolerated doses, AU-4869 exhibited superior efficacy at MTD doses in mice xenograft models (pancreatic cancer and multiple myeloma) as compared to FK866 and GNE-617. In view of the ability of NAMPT inhibitors to enhance sensitivity to a number of targeted agents and overcome resistance to available therapies such as bortezomib in multiple myeloma, further pre-clinical development of AU-4869 for multiple myeloma is ongoing. Citation Format: Dinesh Chikkanna, Anirudha Lakshminarasimhan, Vinayak Khairnar, Sunil panigrahi, Anuradha Ramanathan, Sumalatha Rani, Narasimha Rao, Karthikeyan S, Kishore Narayanan, Sreevalsam Gopinath, Raghuveer Ramachandra, Charamanna K B, Shekar Chelur, Chetan Pandit, Murali Ramachandra. Discovery of dihydro-isoxazole derivatives as novel inhibitors of NAMPT for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5367. doi:10.1158/1538-7445.AM2015-5367