Haberman Victoria A, Fleming Steven R, Leisner Tina M, Puhl Ana C, Feng Emerald, Xie Ling, Chen Xian, Goto Yuki, Suga Hiroaki, Parise Leslie V, Kireev Dmitri, Pearce Kenneth H, Bowers Albert A
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
ACS Med Chem Lett. 2021 Oct 27;12(11):1832-1839. doi: 10.1021/acsmedchemlett.1c00438. eCollection 2021 Nov 11.
Calcium and integrin binding protein 1 (CIB1) is a small, intracellular protein recently implicated in survival and proliferation of triple-negative breast cancer (TNBC). Considering its interactions with PAK1 and downstream signaling, CIB1 has been suggested as a potential therapeutic target in TNBC. As such, CIB1 has been the focus of inhibitor discovery efforts. To overcome issues of potency and stability in previously reported CIB1 inhibitors, we deploy mRNA display to discover new cyclic peptide inhibitors with improved biophysical properties and cellular activity. We advance UNC10245131, a cyclic peptide with low nanomolar affinity and good selectivity for CIB1 over other EF-hand domain proteins and improved permeability and stability over previously identified linear peptide inhibitor UNC10245092. Unlike UNC10245092, UNC10245131 lacks cytotoxicity and does not affect downstream signaling. Despite this, UNC10245131 is a potent ligand that could aid in clarifying roles of CIB1 in TNBC survival and proliferation and other CIB1-associated biological phenotypes.
钙与整合素结合蛋白1（CIB1）是一种小分子细胞内蛋白，最近被认为与三阴性乳腺癌（TNBC）的存活和增殖有关。鉴于其与PAK1及下游信号传导的相互作用，CIB1被认为是TNBC的一个潜在治疗靶点。因此，CIB1一直是抑制剂研发工作的重点。为克服先前报道的CIB1抑制剂在效力和稳定性方面的问题，我们利用mRNA展示技术来发现具有改善的生物物理性质和细胞活性的新型环肽抑制剂。我们推进了UNC10245131的研究，这是一种环肽，对CIB1具有低纳摩尔亲和力，相对于其他EF手型结构域蛋白具有良好的选择性，并且与先前鉴定的线性肽抑制剂UNC10245092相比，其通透性和稳定性有所提高。与UNC10245092不同，UNC10245131没有细胞毒性，也不影响下游信号传导。尽管如此，UNC10245131是一种有效的配体，有助于阐明CIB1在TNBC存活和增殖以及其他与CIB1相关的生物学表型中的作用。
