Open AccessTargeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression
Author(s) -
Lin Qingxiang,
He Yuan,
Wang Xue,
Zhang Yong,
Hu Meichun,
Guo Weikai,
He Yundong,
Zhang Tao,
Lai Li,
Sun Zhenliang,
Yi Zhengfang,
Liu Mingyao,
Chen Yihua
Publication year - 2020
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.201903483
Subject(s) - pyruvate carboxylase , cancer cell , wnt signaling pathway , citric acid cycle , enzyme , metastasis , cancer research , cancer , cell growth , biochemistry , chemistry , breast cancer , biology , signal transduction , genetics
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.