Bhuniya Rajib, Yuan Xinrui, Bai Longchuan, Howie Kathryn L, Wang Rui, Li Wei, Park Frank, Yang Chao-Yie
Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
Department of Internal Medicine, Hematology & Oncology Division, University of Michigan, Ann Arbor, Michigan 48109, United States.
ACS Med Chem Lett. 2022 Jan 18;13(2):188-195. doi: 10.1021/acsmedchemlett.1c00544. eCollection 2022 Feb 10.
CDC20 binds to anaphase-promoting complex/cyclosome E3 ubiquitin ligase to recruit substrates for ubiquitination to promote mitotic progression. In breast and other cancers, CDC20 overexpression causes cell cycle dysregulation and is associated with poor prognosis. Apcin was previously discovered as a CDC20 inhibitor exhibiting high micromolar activities. Here, we designed and developed new apcin-based inhibitors by eliminating a controlled substance, chloral hydrate, required for synthesis. We further improved the antitumor activities of the inhibitors by replacing the pyrimidine group with substituted thiazole-containing groups. When evaluated in MDA-MB-231 and MDA-MB-468 triple negative breast cancer cell lines, several analogs showed 5-10-fold improvement over apcin with IC values at ∼10 μM in cell viability assays. Tubulin polymerization assay showed our CDC20 inhibitors had no off-target effects against tubulin. Proapoptotic Bim accumulation was detected in our CDC20 inhibitor treated MDA-MB-468 cells. The most effective inhibitors, 22, warrant further development to target CDC20 in diseases.
细胞分裂周期蛋白20（CDC20）与后期促进复合物/细胞周期体E3泛素连接酶结合，募集底物进行泛素化，以促进有丝分裂进程。在乳腺癌和其他癌症中，CDC20的过表达会导致细胞周期失调，并与不良预后相关。Apcin先前被发现是一种具有低微摩尔活性的CDC20抑制剂。在此，我们通过去除合成所需的受控物质水合氯醛，设计并开发了基于Apcin的新型抑制剂。我们通过用含取代噻唑的基团取代嘧啶基团，进一步提高了抑制剂的抗肿瘤活性。在MDA-MB-231和MDA-MB-468三阴性乳腺癌细胞系中进行评估时，几种类似物在细胞活力测定中的IC值约为10μM，显示出比Apcin高5至10倍的活性。微管蛋白聚合试验表明，我们的CDC20抑制剂对微管蛋白没有脱靶效应。在我们用CDC20抑制剂处理的MDA-MB-468细胞中检测到促凋亡蛋白Bim的积累。最有效的抑制剂22值得进一步开发，以在疾病中靶向CDC20。
