Abstract LB389: Highly potent and selective RET inhibitor with robust anti-tumor activities against wild-type and acquired drug-resistant mutations

Abstract RET gene mutations and fusions are the driving events for the generation and deterioration of many cancer types. The first generation RET inhibitors, selpercatinib (Loxo-292) and pralsetinib (Blu-667), demonstrated clinically acquired resistance (e. g. , solvent frontier mutations G810X, double mutations V804X-G810X etc. ). Novel treatment that overcomes multiple resistance mutations is needed to improve patient outcomes. Leveraging our in-house AI technology platform, we have discovered the next generation RET inhibitors that overcome multiple resistance mutations including solvent front, gatekeeper and various double mutations. We employ the synergistic advantages of domain expertise and modern technology to accelerate early stage drug discovery. On our deep learning (DL) centric AI platform, extensive scientific computing supports large scale virtual screening, generative design, drug property prediction and multi-objective lead optimization. Only the optimized candidate compounds are passed along for synthesis and testing to save time and cost. In cell proliferation assays, our compound effectively inhibited KIF5B-RET Ba/F3 WT, V804M, G810S, G810R, V804M-G810S with IC50 values of 0. 4 nM, 1. 3 nM, 1. 1 nM, 3. 4 nM, 6. 3 nM, respectively, demonstrating significant improvement over selpercatinib in the range of several hundred fold in activities. Importantly, the compound is highly selective against VEGFR2, an off-target responsible for cardiovascular adverse effects in the approved RET inhibitors. The superior cellular potencies translated consistently into animal models. In Ba/F3 KIF5B-RET-G810R xenograft model, treatment of 25 mg/kg bid resulted in 90% TGI with a100% survival rate. The compound showed favorable pharmacokinetic properties, lack of drug-drug interaction (DDI), and devoid of hERG liability (IC50 10uM). Preclinical safety evaluations in rats exhibited good tolerance margin. We have discovered the second generation compound that potently inhibits a diverse range of RET alterations. The compound exhibits preferable pharmaceutical profiles and is advancing toward IND application. Citation Format: Li Xing, Wei Zhu, Jingbing Wang. Highly potent and selective RET inhibitor with robust anti-tumor activities against wild-type and acquired drug-resistant mutations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB389.