Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression
Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression
复制标题
通过小分子靶向丙酮酸羧化酶抑制癌症进展
DOI：
10.1002/advs.201903483
复制
发表时间：
2020-05-01
期刊：
影响因子：
15.1
通讯作者：
Chen, Yihua
中科院分区：
文献类型：
--
作者：
Lin, Qingxiang;He, Yuan;Chen, Yihua
快速代谢将癌细胞与正常细胞区分开来，并依赖于突变途径。然而，过敏相关酶的机制很少被理解。缺乏有效和选择性的抗代谢药物限制了进一步的临床研究。发现一种小分子ZY-444 （（N-4-（5-（4-（苯氧基）苯基）-2-噻吩基）甲基）- n -2-异丁基-2,4-嘧啶二胺）特异性抑制癌细胞增殖，对肿瘤生长、转移和复发具有有效的抑制作用。ZY-444与细胞丙酮酸羧化酶（PC）结合，使其催化活性失活，PC是三羧酸循环的关键复联酶。PC抑制通过抑制Wnt/ β -catenin/Snail信号通路抑制乳腺癌的生长和转移。肿瘤患者中较低的PC表达与显著的生存益处相关。癌组织与正常组织中PC表达的对比表明ZY-444具有肿瘤选择性。总的来说，ZY-444作为抗癌代谢药物具有治疗前景。
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/beta-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.