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Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression.
Advanced Science ( IF 14.3 ) Pub Date : 2020-03-12 , DOI: 10.1002/advs.201903483 Qingxiang Lin 1 , Yuan He 1, 2 , Xue Wang 1 , Yong Zhang 1 , Meichun Hu 1 , Weikai Guo 1 , Yundong He 1 , Tao Zhang 1 , Li Lai 1 , Zhenliang Sun 2 , Zhengfang Yi 1, 2 , Mingyao Liu 1 , Yihua Chen 1
Advanced Science ( IF 14.3 ) Pub Date : 2020-03-12 , DOI: 10.1002/advs.201903483 Qingxiang Lin 1 , Yuan He 1, 2 , Xue Wang 1 , Yong Zhang 1 , Meichun Hu 1 , Weikai Guo 1 , Yundong He 1 , Tao Zhang 1 , Li Lai 1 , Zhenliang Sun 2 , Zhengfang Yi 1, 2 , Mingyao Liu 1 , Yihua Chen 1
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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.
中文翻译：
通过小分子靶向丙酮酸羧化酶抑制乳腺癌进展。
快速代谢将癌细胞与正常细胞区分开来，并依赖补补途径。然而，回补相关酶的机制很少被了解。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。小分子 ZY-444 ((N 4-((5-(4-(benzyloxy)苯基)-2-thio苯基)methyl)-N 2-iso丁基-2,4-pyrimidinediamine) 被发现可以特异性抑制癌细胞增殖，对肿瘤生长、转移和复发具有有效功效，ZY-444 与细胞丙酮酸羧化酶 (PC)（三羧酸循环的关键回补酶）结合，并通过抑制 PC 抑制其催化活性来抑制乳腺癌生长和转移。抑制患者肿瘤中的 Wnt/β-连环蛋白/Snail 信号通路与显着的生存益处相关，癌症与正常组织中 PC 表达的比较表明 ZY-444 具有肿瘤选择性。有望作为抗癌代谢剂进行治疗。
更新日期：2020-03-12
中文翻译：
通过小分子靶向丙酮酸羧化酶抑制乳腺癌进展。
快速代谢将癌细胞与正常细胞区分开来，并依赖补补途径。然而，回补相关酶的机制很少被了解。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。小分子 ZY-444 ((N 4-((5-(4-(benzyloxy)苯基)-2-thio苯基)methyl)-N 2-iso丁基-2,4-pyrimidinediamine) 被发现可以特异性抑制癌细胞增殖，对肿瘤生长、转移和复发具有有效功效，ZY-444 与细胞丙酮酸羧化酶 (PC)（三羧酸循环的关键回补酶）结合，并通过抑制 PC 抑制其催化活性来抑制乳腺癌生长和转移。抑制患者肿瘤中的 Wnt/β-连环蛋白/Snail 信号通路与显着的生存益处相关，癌症与正常组织中 PC 表达的比较表明 ZY-444 具有肿瘤选择性。有望作为抗癌代谢剂进行治疗。
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