Mendoza Manuel, Tran UyenPhuong, Zhang Grace C, Leister Jeffrey, To Kyle, Malepeai-Tofaeono Theodore, Ondrus Alison E, Billingsley Kelvin L
Department of Chemistry and Biochemistry, California State University Fullerton, Fullerton, California 92831, United States.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
ACS Med Chem Lett. 2022 Jun 3;13(7):1036-1042. doi: 10.1021/acsmedchemlett.1c00562. eCollection 2022 Jul 14.
The Gli transcription factors within the Hedgehog (Hh) signaling pathway play essential roles in human development. However, the reactivation of Gli proteins in adult tissue is tumorigenic and drives the progression of several cancers, including the majority of basal cell carcinomas. Here we describe a novel set of indolactam dipeptides that target protein kinase C (PKC), exploiting the unique capacity of PKC isozymes to act as regulators of Gli. We devised an efficient synthetic route for the indolactam-based natural product (-)-pendolmycin and a series of analogues, and we evaluated these analogues in mechanistically distinct Gli reporter assays. The lead compound from these studies, -hexylindolactam V, exhibits superior Gli suppression relative to clinical inhibitors and blocks the growth of Gli-dependent basal cell carcinoma cells. More broadly, our structure-activity studies provide inroads for the development of novel Gli antagonists and new avenues for combating Gli-driven cancers.
刺猬索尼克（Hh）信号通路中的Gli转录因子在人类发育过程中发挥着至关重要的作用。然而，Gli蛋白在成体组织中的重新激活具有致瘤性，并推动包括大多数基底细胞癌在内的多种癌症的进展。在此，我们描述了一组新型的吲哚内酰胺二肽，它们靶向蛋白激酶C（PKC），利用PKC同工酶作为Gli调节剂的独特能力。我们设计了一种高效的合成路线来制备基于吲哚内酰胺的天然产物（-）-pendolmycin及其一系列类似物，并在机制不同的Gli报告基因检测中对这些类似物进行了评估。这些研究中的先导化合物——己基吲哚内酰胺V，相对于临床抑制剂表现出卓越的Gli抑制作用，并能阻断Gli依赖性基底细胞癌细胞的生长。更广泛地说，我们的构效关系研究为新型Gli拮抗剂的开发提供了途径，也为对抗Gli驱动的癌症开辟了新的道路。
