Abstract 1419: RCZY-711, a novel, highly potent, and orally bioavailable menin-MLL inhibitor with superior efficacy in preclinical acute leukemia models

Abstract Menin, encoded by the MEN1 gene, is a scaffold protein widely expressed in human tissues, regulating diverse functions through interactions in key signaling pathways. The menin-MLL1 (KMT2A) complex plays a critical role in acute leukemias with KMT2A rearrangements or NPM1 mutations, driving aberrant expression of HOX genes and MEIS1, which promote leukemia development. MLL is a histone H3K4 methyltransferase essential for transcription in embryonic development and hematopoiesis and frequently forms oncogenic fusion proteins via chromosomal translocations. Disrupting the menin-MLL interaction is an effective therapeutic strategy for MLL-rearranged and NPM1-mutant leukemias. The FDA-approved menin inhibitor SNDX-5613 treats relapsed/refractory acute leukemia with MLL translocations, while ongoing trials explore its use in KRAS-mutant solid tumors and Wnt-driven cancers. Another menin inhibitor, KO-539, is being tested in advanced gastrointestinal stromal tumors. Developing novel menin inhibitors with enhanced safety and efficacy remains a significant clinical priority. Herein, we report RCZY-711, a novel, highly potent, and orally bioavailable menin inhibitor with subnanomolar binding affinity, as demonstrated by SPR. Its potency in disrupting the menin-MLL interaction was further validated using a fluorescence polarization assay (subnanomolar IC50). RCZY-711 displayed potent growth inhibition (single-digit nanomolar IC50) in cancer cell lines with KMT2A rearrangements or NPM1 mutations, without cytotoxicity in wild-type MLL cell lines. The compound demonstrated desirable drug-like in vitro ADME characteristics, clean in vitro safety characteristics (hERG IC50 > 20 µM), and excellent pharmacokinetic characteristics across multiple preclinical species. Oral treatment with RCZY-711 also showed strong in vivo anti-tumor efficacy in acute myeloid leukemia xenograft mouse models, including the MV-4-11 xenograft model with the MLL-AF4 fusion. The observed superior in vivo efficacy may be attributed to its high cellular potency and improved half-life (mouse: T1/2 = 2.0 h). In conclusion, RCZY-711 is a novel, highly potent and orally bioavailable menin-MLL inhibitor with best-in-class clinical potential for treating MLL-rearranged and NPM1-mutant acute leukemias. Citation Format: Celia X.-J. Chen, Zhengyong Wan, Yu Bai, Xiaohong Liu, Jianming Bao. RCZY-711, a novel, highly potent, and orally bioavailable menin-MLL inhibitor with superior efficacy in preclinical acute leukemia models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1419.