Abstract LB_C10: An orally available small molecule inhibitor for synthetic lethal targeting of MYC expressing tumors

Abstract

Abstract The potential for synthetic lethality occurs when the same oncogenic events that promote carcinogenesis, also create vulnerabilities for cancer cells. Targeting cancers with these vulnerabilities, but not resident normal tissues, is the promise of synthetic lethal therapies. The compound LC30 is a potent and orally bioavailable compound that is synthetic lethal with deregulated MYC. No off-target liabilities have been demonstrated by kinome and safety profiling and long-term treatment is well tolerated by rodents and canines. LC30 is active against a wide spectrum of cell line xenografts derived from both liquid and solid cancers, including B and T cell malignancies, lung, colon, gastric, mammary and liver cancer cell lines, with efficacy that correlates with levels of MYC. Experiments aimed at unlocking the key to LC30’s synthetic lethality have revealed that LC30 is active in both resting cells and during cell division, so it is not simply an anti-mitotic compound. In resting cells, LC30 disrupts golgi structure, a phenotype that possibly relates to MYC control of centrosomal gene expression. Anti-angiogenic effects are observed in xenografts and have been confirmed using in vitro assays of endothelial cell migration and tubule formation. We speculate that the golgi phenotype and resulting faulty trafficking of secretory vesicles containing pro-angiogenic factors may underly the vascular phenotype. In dividing cells, LC30 potently deregulates the positioning of the chromosomal passenger protein complex (CPPC), a mitotic complex comprised of a catalytic subunit, Aurora B kinase (AURKB), the scaffolding protein inner centromere protein (INCENP) as well as survivin and borealin. The CPPC is dynamically relocated during mitotic progression so that AURKB activity can be localized to specific locations where activity is required. The phenotypic effects of LC30 treatment are consistent with this compound functioning as an inhibitor of the localization, but not catalytic activity of the CPPC. This includes the induction of multipolar spindles, micronuclei and polyploidy, leading to mitotic arrest and both mitotic and post-mitotic apoptosis. This unique mode-of-action, to disrupt CPPC passage in the mitotic cell, is a key component of the MYC synthetic lethality as cells without MYC overexpression do not develop multipolar spindles, lethal polyploidy and apoptose with treatment. LC30 represents a new class of anticancer compound that is a non-kinase, synthetic lethal inhibitor that unlocks MYC-induced vulnerabilities in cancer cells. Citation Format: Qiong Shi, Ting Zhang, Julia Kalashova, Jinhua Li, Chenglu Yang, Hongmei Li, Xiaohu Zhou, Yan Long, Yidan Xia Abuliezi, Gang Lv, Duo Yu, Shenqiu Zhang, Jing Zhang, Thaddeus D Allen, Hong Liu, Dun Yang. An orally available small molecule inhibitor for synthetic lethal targeting of MYC expressing tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C10.