TY - JOUR
T1 - Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression
AU - Lin, Qingxiang
AU - He, Yuan
AU - Wang, Xue
AU - Zhang, Yong
AU - Hu, Meichun
AU - Guo, Weikai
AU - He, Yundong
AU - Zhang, Tao
AU - Lai, Li
AU - Sun, Zhenliang
AU - Yi, Zhengfang
AU - Liu, Mingyao
AU - Chen, Yihua
N1 - Funding Information:
The authors thank Dr. Stefan Siwko (Texas A&M University, USA) for revising this paper. This work was partially supported by the grants from National Key R&D Program of China (Grant No. 2018YFA0507001), National Natural Science Foundation of China (Grant Nos. 81773204, 81673304, 81973160, 81830083, and 81872418), Innovation program of Shanghai municipal education commission (Grant No. 2017-01-07-00-05-E00011), Shenzhen Municipal Government of China (Grant No. KQTD20170810160226082), and ECNU Public Platform for innovation (011).
Publisher Copyright:
© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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 ((N4-((5-(4-(benzyloxy)phenyl)-2-thiophenyl)methyl)-N2-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.
AB - 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 ((N4-((5-(4-(benzyloxy)phenyl)-2-thiophenyl)methyl)-N2-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.
KW - breast cancer
KW - cancer metabolism
KW - pyruvate carboxylase
KW - small molecule ZY-444
KW - Wnt/β-catenin/Snail pathway
UR - http://www.scopus.com/inward/record.url?scp=85081750382&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85081750382&partnerID=8YFLogxK
U2 - 10.1002/advs.201903483
DO - 10.1002/advs.201903483
M3 - Article
AN - SCOPUS:85081750382
SN - 2198-3844
VL - 7
JO - Advanced Science
JF - Advanced Science
IS - 9
M1 - 1903483
ER -