Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression
- Adv Sci (Weinh). 2020 Mar 12;7(9):1903483. doi: 10.1002/advs.201903483.
- 1. East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P. R. China.
- 2. Joint Center for Translational Medicine Southern Medical University Affiliated Fengxian Hospital Shanghai 201499 P. R. China.
Rapid metabolism differentiates Cancer cells from normal cells and relies on anaplerotic pathways. However, the mechanisms of anaplerosis-associated Enzymes are rarely understood. The lack of potent and selective antimetabolism drugs restrains further clinical investigations. A small molecule ZY-444 ((N 4-((5-(4-(benzyloxy)phenyl)-2-thiophenyl)methyl)-N 2-isobutyl-2,4-pyrimidinediamine) is discovered to inhibit Cancer cell proliferation specifically, having potent efficacies against tumor growth, metastasis, and recurrence. ZY-444 binds to cellular pyruvate carboxylase (PC), a key anaplerotic enzyme of the tricarboxylic acid cycle, and inactivates its catalytic activity. PC inhibition suppresses breast Cancer growth and metastasis through inhibiting the Wnt/β-catenin/Snail signaling pathway. Lower PC expression in patient tumors is correlated with significant survival benefits. Comparative profiles of PC expression in Cancer versus normal tissues implicate the tumor selectivity of ZY-444. Overall, ZY-444 holds promise therapeutically as an anti-cancer metabolism agent.