Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression.

Qingxiang Lin,Yundong He,Tao Zhang,Mingyao Liu,Yihua Chen,Meichun Hu,Weikai Guo,Zhengfang Yi,Zhenliang Sun,Li Lai,Xue Wang,Yuan He,Yong Zhang

doi:10.1002/advs.201903483

Abstract

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.

Highlights

Rapid metabolism differentiates cancer cells from normal cells and relies metabolic intermediates for tumor growth and metastasis.[3]
We hypothesized that compound tumor selectivity could partly result from differential metabolism in tumor cells versus normal cells
It gives rise to the development of cancer therapeutics that function by targeting glycolysis.[17a,18,21,42b,43] recent studies have expanded the notion that accelerated glycolysis is predominantly a partial accompanying mechanism for energy requirements of proliferation, and that replenishing biosynthetic macromolecules through anaplerotic pathways is vital for rapid tumor growth.[3b,5,44]

Summary

Introduction

Rapid metabolism differentiates cancer cells from normal cells and relies metabolic intermediates for tumor growth and metastasis.[3]. 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 having potent efficacies against tumor growth, the biosynthetic precursor molecules to the tricarboxylic acid cycle (TCA), such as oxaloacetate and glutamine,[3a,5] as well as essential intermediates of the mitochondrial electron chain.[6]. ZY-444 binds to cellular pyruvate carboxylase with the high glycolytic flux, a high (PC), a key anaplerotic enzyme of the tricarboxylic acid cycle, and inactivates its catalytic activity. Lower PC expression in patient tumors is correlated with significant survival anaplerotic flux could indicate excessive cancer proliferation.[7]. Two enzymes that play indispensable roles in anaplerosis of TCA intermediates are glutaminase and pyruvate carboxylase benefits. Compared with non-cancerous tissues, PC expression is greatly enhanced in patients. Oncogenetic reprogramming of cancer metabolism favors the by PC knockdown is accompanied by disrupted TCA activity

Results

Discussion

Conclusion