Abstract 5990: Microtubule-associated serine/threonine kinase-likeinhibitor, AD1208, as a novel cancer therapeutics

Abstract

Abstract Microtubule-associated serine/threonine kinase-like is an essential regulator of mitosis and emerged as a novel oncogenic kinase. It is upregulated in several cancer types, correlating with chromosome instability and poor patient survival. Here, we are reporting a MASTL inhibitor, AD1208, as a new cancer therapeutics.AD1208 inhibits kinase activity of MASTL with IC50 value of 7nM in competitive manner against ATP and induces apoptosis of colorectal cancer cells with IC50 of 150nM. Selectivity index is higher than 100 folds when the cytotoxicity was measured in normal colon cells. Synthetic lethality with BRCA was observed in knock out studies. Cell panel analysis, consist of 300 cell lines, indicated that the AD1208 is effective in cancers originated from stomach, colon, leukemia, lymphoma, and soft tissue. In vivo efficacy was confirmed in mouse xenograft model in dose dependent manner and synergistic effect with PARP inhibitor was observed. Kinase Assay Panel screening revealed that AD1208 is highly selective against 468 kinases. Inhibition of MASTL resulted in decreasing phosphorylated ENSA, inactivating CDK1 and arresting cell cycle progression at G2/M phase. Clinical adverse drug reactions of AD1208 were predicted by in vitro Safety Functional Panel screening to exhibit no meaningful safety-related issues. Currently, AD1208 is being conducted in IND enabling GLP-Tox studies, including genotoxicity, mutagenicity, safety pharmacology as well as in vivo safety studies. Taken together, AD1208 is identified as a novel and selective MASTL inhibitor exhibiting significant therapeutic potential to be a development candidate. Citation Format: SOONGYU CHOI, JS Ahn, KS Baek, YL Choi, MY Im, JH Kim, JW Kim, JH Khoo, SH Lee, WL Yao, Young-Whan Park. Microtubule-associated serine/threonine kinase-likeinhibitor, AD1208, as a novel cancer therapeutics [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 5990.