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Discovery and Development of Cyclic Peptide Inhibitors of CIB1.

Authors :: Haberman VA
Fleming SR
Leisner TM
Puhl AC
Feng E
Xie L
Chen X
Goto Y
Suga H
Parise LV
Kireev D
Pearce KH
Bowers AA
Source :: ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Oct 27; Vol. 12 (11), pp. 1832-1839. Date of Electronic Publication: 2021 Oct 27 (Print Publication: 2021).
Publication Year :: 2021
Abstract: 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.<br />Competing Interests: The authors declare no competing financial interest.<br /> (© 2021 American Chemical Society.)