Abstract 2113: HMPL-506, a novel, highly potent and differentiated menin-MLL inhibitor for the treatment of MLL-rearrangedand NPM1mutant acute leukemia in preclinical models

Abstract Background: Mixed-lineage leukemia (MLL, or KMT2A) gene rearrangements (MLL-r) occur in 5%-10% acute leukemias and are associated with poor prognosis. Nucleophosmin 1 mutations (NPM1m) are the most common genetic alterations in acute myeloid leukemia (AML). Multiple studies have illuminated that those leukemogenesis are dependent on the interaction of menin-MLL, which controls downstream gene expressions associated with cell proliferation and differentiation, e.g. HOXA9 and CD11b. Herein, we introduce HMPL-506, a novel and highly differentiated small molecule compound targeting menin-MLL interaction. Methods and Results: Biochemical assay revealed that HMPL-506 potently blocked menin-MLL binding with IC50 of 1.0 nM. In cell lines carrying MLL-r or NPM1m, HMPL-506 substantially down-regulated menin-MLL target genes transcription of MEIS1 and HOXA9 and upregulated the differentiation marker of CD11b by RT-PCR assay, consequently, HMPL-506 attenuated tumor cell growth, with GI50 ranging from 3.0 to 12.1 nM in MLL-r cell lines (MV-4-11, MOML-13 and RS4;11) and 22.4 nM in NPM1m cell line (OCI-AML-3) in CellTiter-Glo cell viability assay. Notably, compared with the other 5 menin inhibitors in clinical stage, HMPL-506 showed the strongest inhibitory potency in MLL-r and NPM1m cell line models. In vivo studies demonstrated the dose- and exposure- dependent target regulation of MEIS1 and anti-tumor efficacy following HMPL-506 treatment in multiple tumor xenograft models. For instance, in MV-4-11 subcutaneous model, once daily oral administration of HMPL-506 at 5, 10 and 25 mg/kg for 4 days in BALB/c nude mice induced dose-dependent inhibition of MEIS1 gene expression, positively correlating with compound exposures in tumor tissues; continuous dosing of HMPL-506 at 5 mg/kg for 28 days reduced the tumor growth by 86%, which was comparable to the efficacy induced by SNDX-5613 at 50 mg/kg. Treatment of HMPL-506 at 10 mg/kg and 25 mg/kg resulted in tumor shrinkage in all treated animals, with tumor regression rates of 72% and 100%, respectively. Furthermore, HMPL-506 synergistically improved anti-tumor effect of azacytidine, venetoclax and gilteritinib against MLL-r leukemias both in vitro and in vivo. HMPL-506 displayed favorable PK profiles and high selectivity among multiple kinases, methyltransferases and safety related targets. More importantly, the IC50 of HMPL-506 on hERG patch clamp was over 60 µM, indicating low risk of QTc prolongation in human. Conclusion: HMPL-506 is a novel and highly differentiated menin-MLL inhibitor with robust anti-tumor activities, favorable ADME properties and low risk of cardiac toxicity, warranting it further clinical development for treatment of MLL-r and NPM1m acute leukemias. HMPL-506 IND is expected to be cleared in H1 2024. Citation Format: Min Cheng, Liang Ge, Zhihu Gao, Zeyu Zhong, An Jiang, Wei Zhang, Jia Hu, Shuwen Jiang, Na Li, Na Yang, Jian Wang, Yang Sai, Weiguo Qing, Yongxin Ren, Weiguo Su. HMPL-506, a novel, highly potent and differentiated menin-MLL inhibitor for the treatment of MLL-rearrangedand NPM1mutant acute leukemia in preclinical 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 2113.