Discovery and Development of Cyclic Peptide Inhibitors of CIB1

Victoria A Haberman; Steven R Fleming; Tina M Leisner; Ana C Puhl; Emerald Feng; Ling Xie; Xian Chen; Yuki Goto; Hiroaki Suga; Leslie V Parise; Dmitri Kireev; Kenneth H Pearce; Albert A Bowers

doi:10.1021/acsmedchemlett.1c00438

Discovery and Development of Cyclic Peptide Inhibitors of CIB1

ACS Med Chem Lett. 2021 Oct 27;12(11):1832-1839. doi: 10.1021/acsmedchemlett.1c00438. eCollection 2021 Nov 11.

Authors

Victoria A Haberman^{1

2}, Steven R Fleming^{1

2}, Tina M Leisner^{2

3}, Ana C Puhl², Emerald Feng³, Ling Xie³, Xian Chen^{3

4}, Yuki Goto^{5

6}, Hiroaki Suga^{5

7}, Leslie V Parise^{3

4}, Dmitri Kireev², Kenneth H Pearce^{2

4}, Albert A Bowers^{1

2

4}

Affiliations

¹ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
² Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
³ Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
⁵ Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
⁶ JST, PRESTO, Tokyo 113-0033, Japan.
⁷ JST, CREST, Tokyo 113-0033, Japan.

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.

Abstract

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