Abstract 1752: SY-13380, a novel menin-MLL inhibitor, exhibits efficacy against resistant mutations and anti-tumor activity for MLL-rearranged and NPM1-mutant acute myeloid leukemia in pre-clinical models

Abstract The menin-KMT2A interaction is a critical epigenetic regulator for leukemogenesis in many acute leukemias, including KMT2A-rearranged (KMT2Ar) acute leukemia and NPM1-mutant (NPM1m) acute myeloid leukemia (AML). Patients with these alterations always have dismal response rates and poor prognosis. Some selective inhibitors of the menin-KMT2A complex have demonstrated encouraging activity in patients with R/R AML. However, early trials with revumenib have reported the rapid acquisition of resistance somatic mutations of MEN1 gene in about 40% patients which can impair treatment success. Herein, we introduce SY-13380, a novel menin-MLL inhibitor, exhibits potent binding affinity against wild type and resistant mutations and displayed excellent anti-tumor activity in pre-clinical models. Biochemical assay revealed that SY-13380 potently blocked menin-MLL binding with an IC50 under 10.0 nM, and it also displayed very strong potency on series of resistant mutants (M327I, M327V, G331R and T349M) similar to that on WT proteins. In cellular assays, SY-13380 also strongly inhibited cell proliferation in multiple cancer cell lines carrying KMT2Ar or NPM1m, especially in M327I mutant MOLM13 cells which was insensitive to approved Menin inhibitor SNDX-5613. In cell functional studies, SY-13380 dose-dependently down-regulated menin-MLL target gene HOXA9 and MEIS1, and induced the expression of differentiation marker CD11b. In vivo studies showed that treatment of SY-13380 achieved excellent tumor growth inhibition in various xenograft tumor models including MV-4-11, RS4;11, OCI AML3 and MOLM13 harboring M327I mutant menin. Notably, tumor regression was found in MV-4-11 xenograft tumor models after treatment with SY-13380 at dosage of 10mpk. In addition, SY-13380 displayed good PK parameters and tolerability in vitro and in vivo models. These data indicate that SY-13380 is a novel and potent menin-MLL inhibitor with robust anti-tumor activities, favorable PK and safety profiles making it promising for further clinical development and efficacy against resistant mutations warranting it long-term response for treatment of MLL-r and NPM1m acute leukemias. Citation Format: Xiaopeng Li, Tiantian Hao, Hongjuan Li, Chang Lu, Shikang Cheng, Xinhe Xu, Huiyan Luo, Xijie Liu, Hong Luo, Yinghui Sun. SY-13380, a novel menin-MLL inhibitor, exhibits efficacy against resistant mutations and anti-tumor activity for MLL-rearranged and NPM1-mutant acute myeloid leukemia in pre-clinical 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 1752.