Abstract 611: Discovery of LNX231, a multi-kinase inhibitor mainly target FLT3 with robust in vivo efficacy in FLT3 mutant AML models

Abstract LNX231 is a multi-kinase inhibitor mainly target FLT3, which could both directly kill cancer cells and promote tumor immunity. LNX231 potently inhibits FLT3 activity in biochemical assay, with a 50% inhibitory concentration (IC50) of 3.5 nM, significantly inhibits FLT3-D835Y and FLT3 ITD, the values of IC50 are 20 nM and 4.4 nM. LNX231 inhibits the proliferation of FLT3 mutant AML cell lines via RAS-MARK and JAK-STAT pathway. LNX231 significantly decreases the phosphorylation of STAT5 and ERK in MV-4-11 cells at the high concentration, but has no effect on the phosphorylation of FLT3 and AKT. LNX231 significantly decreases the phosphorylation of FLT3, STAT5 and ERK in MOLM-13 cells at the high concentration, but has no effect on the phosphorylation of AKT. In FLT3 mutated AML models, LNX231 induced sustained tumor shrinkage as a single agent and was well tolerated. At the same dose, LNX231 was more potent than the FDA-approved drug Gilteritinib. In the MC38 tumor-bearing model, the efficacy of LNX231 was better than Sunitinib and Lenvatinib. LNX231 has good oral bioavailability in different species, such as mouse, rat, dog and monkey. DMPK data predicted oral QD dosing in human. It also showed excellent ADMET profile as a pre-clinical candidate. Safety tolerability studies were conducted in mice and dogs. LNX231 has low cardiotoxicity (IC50 of hERG is 25.84 µM) and 5-6 times safety window. In conclusion, we discovered LNX231 as a multi-kinase inhibitor for FLT3 mutated AML. Citation Format: Lizhi Zhao, Guizhou Hao, Rong Deng, Naihua Zhang, Jingchun Yao, Anguo Zhu, Guangyan Li, Enli Wang, Zhenyu Li, Zhong Liu, Guimin Zhang. Discovery of LNX231, a multi-kinase inhibitor mainly target FLT3 with robust in vivo efficacy in FLT3 mutant AML models [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(6_Suppl):Abstract nr 611.