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Abstract Rearranged during transfection (RET) is a protein tyrosine kinase that is aberrantly activated by gene fusions or mutations in many types of human cancer including thyroid cancer and non-small cell lung cancer (NSCLC). Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are FDA approved RET-selective tyrosine kinase inhibitors (TKIs) being used to treat RET-altered cancer. However, these tumors develop selpercatinib/pralsetinib-resistance via acquisition of RET (G810C/R/S) mutations located at the solvent front of the ATP binding pocket. The overall goal of our research is to discover next-generation of RET kinase inhibitors to inhibit selpercatinib/pralsetinib-resistant RET solvent-front mutants. In this study, we characterized one of the nicotinamide-based RET kinase inhibitor, HSN748, in vitro and in vivo. HSN748 was able to inhibit selpercatinib/pralsetinib-resistant RET (G810C/R) solvent-front mutations. In BaF3/KIF5B-RET (G810C) tumor xenograft experiment, HSN748 treatment resulted in tumor regression. In immune competent transgenic mice, KIF5B-RET-induced lung tumors regressed after HSN748 treatment by oral gavage for one month (10-15 mg/kg, QD) without affecting body weight. These results identify HSN748 as an orally available RET inhibitor capable of inhibiting KIF5B-RET and its solvent-front mutant-driven tumors. Citation Format: Ujjwol Khatri, Neetu Dayal, Tao Shen, Xueqing Hu, Herman Sintim, Jie Wu. Characterization of a nicotinamide-based kinase inhibitor HSN748 for inhibition of RET-driven tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4660.
Khatri et al. (Fri,) studied this question.