Abstract LB526: HBI-2375, a selective inhibitor of MLL1-WDR5 interaction, possesses desirable preclinical characteristics to be pursued in IND enabling studies and future clinical investigations

Abstract

Abstract 92130MLL1 (mixed lineage leukemia1) interaction with WDR5 (WD repeat domain 5) is critical for MLL1 histone methyl transferase (H3K4me) activity leading to transcriptional regulation of gene expression. MLL1 dysregulation such as its translocation at chromosome 11q23 results in generation of MLL1 fusion genes and leukemia development. Additionally, recent studies indicated a role for MLL1-WDR5 interaction in solid tumors progression via directly affecting cancer cells or by suppression of tumor immunity. Therefore, MLL1-WDR5 interaction is an important target in cancer drug discovery, both in leukemia and in solid tumors. HUYABIO recently completed acquisition of a novel series of MLL1-WDR5 inhibitors and conducted an additional SAR campaign to identify a lead compound with greater efficacy and PK (pharmacokinetics)characteristics. Characterization of a series of analogs identified HBI-2375 as a selective inhibitor of MLL1-WDR5 interaction. TR-FRET peptide binding assay indicated potent binding of HBI-2375 to WDR5 (IC50=4.48 nM) and in vitro cell potency studies showed inhibition of proliferation in MV4;11 leukemia cells by HBI-2375 (IC50=3.17 µM).Furthermore, HBI-2375 was stable in liver S9 and whole blood and displayed reasonable PK properties (Cmax, T1/2, AUC and F%) in preclinical testing in mouse and dog. In vivo efficacy studies in MV4;11 model showed 86% and 77% tumor growth inhibition in HBI-2375 treated tumors when dosed at 80 mpk or 40 mpk (po, qd x 21) respectively. In addition, HBI-2375 was found to be well tolerated since body weight data in the recipients did not show a significant change throughout the treatment. Interestingly, ex vivo tumor analysis showed a reduction in H3K4me in both 40 and 80 mpk samples, further validating target-driven activity of HBI-2375. These data resulted in the nomination of HBI-2375 as the lead clinical candidate for the current IND enabling studies and future investigations in the clinic. Citation Format: Farbod Shojaei, J E. Semple, Che Fang, Jill M. Ricono, Fairooz Kabbinavar, Bob Goodenow, Mireille Gillings. HBI-2375, a selective inhibitor of MLL1-WDR5 interaction, possesses desirable preclinical characteristics to be pursued in IND enabling studies and future clinical investigations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB526.