On September 12, 2023 Exelixis, Inc. (Nasdaq: EXEL) and Insilico Medicine ("Insilico") reported that the companies have entered into an exclusive license agreement granting Exelixis global rights to develop and commercialize ISM3091, a potentially best-in-class small molecule inhibitor of USP1, which has emerged as a synthetic lethal target in the context of BRCA-mutated tumors (Press release, Exelixis, SEP 12, 2023, View Source [SID1234635101]).
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Under the terms of the agreement, Insilico granted Exelixis an exclusive, worldwide license to develop and commercialize ISM3091, and other USP1-targeting compounds, in exchange for an upfront payment to Insilico of $80 million anticipated in the third quarter 2023. Insilico is also eligible to receive future development, commercial, and sales-based milestone payments, as well as tiered royalties on net sales.
"ISM3091 represents a potentially best-in-class approach to inhibiting USP1, an important oncology target with broad applicability in BRCA-mutant tumors," said Dana Aftab, Ph.D., Executive Vice President, Discovery and Translational Research and Chief Scientific Officer, Exelixis. "We believe preclinical data on ISM3091’s potent anti-tumor activity, tolerability, and pharmacokinetics set the compound apart from competing USP1 inhibitors and make it an important addition to Exelixis’ growing clinical-stage pipeline. Following the FDA’s clearance of Insilico’s IND earlier this spring, we’re looking forward to accelerating phase 1 trial enrollment."
"ISM3091 is the third clinical-stage program made possible by Chemistry42, Insilico Medicine’s generative AI platform for small molecule drug discovery," said Alex Zhavoronkov, Ph.D., founder and CEO of Insilico Medicine. "The compound’s novel structure, anti-tumor activity, and excellent drug-like properties give it significant potential as a differentiated program directed at BRCA-mutant tumors, which include forms of ovarian, prostate, and breast cancer. This program attracted significant interest from multiple potential partners in the pharmaceutical industry, but we were most impressed by the level of technical expertise and development and commercial capabilities of Exelixis. With a track record of commercial and clinical development success in oncology, Exelixis is the best partner to take ISM3091 forward, and we’re excited to see the program take flight as a component of the company’s pipeline behind cabozantinib, its global oncology franchise."
USP1 facilitates DNA damage repair by removing ubiquitin from multiple substrates including proteins that stabilize the replication fork. A small molecule discovered using Insilico Medicine’s generative AI platform with extensive multiparameter optimization capabilities, ISM3091 was designed to inhibit the activity of USP1. In preclinical experiments, ISM3091 was found to be potently efficacious against multiple tumor cell lines and in vivo models with BRCA mutations, as well as in homologous recombination DNA repair (HRR)-proficient models, both as a single agent and in combination with PARP inhibitors. It is also well tolerated in different species with a high margin of safety. Insilico disclosed select data in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2023. On April 17, 2023, the FDA cleared the initial IND for ISM3091 for the treatment of patients with solid tumors.