Identification of a potent and selective covalent Pin1 inhibitor.

Autor: Pinch BJ; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Doctor ZM; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Nabet B; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Browne CM; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.; Discovery Biology, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Boston, MA, USA., Seo HS; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Mohardt ML; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Kozono S; Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Lian X; Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Manz TD; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.; Department of Pharmacological and Medicinal Chemistry, Saarland University, Saarbruecken, Germany., Chun Y; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Kibe S; Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Zaidman D; Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel., Daitchman D; Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel., Yeoh ZC; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Vangos NE; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Geffken EA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Tan L; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Ficarro SB; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA., London N; Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel., Marto JA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Buratowski S; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Dhe-Paganon S; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Zhou XZ; Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Lu KP; Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. klu@bidmc.harvard.edu., Gray NS; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. Nathanael_Gray@dfci.harvard.edu.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Nathanael_Gray@dfci.harvard.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2020 Sep; Vol. 16 (9), pp. 979-987. Date of Electronic Publication: 2020 Jun 01.
DOI: 10.1038/s41589-020-0550-9
Abstrakt: Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer. In parallel to inhibitor development, we employed genetic and chemical-genetic strategies to assess the consequences of Pin1 loss in human PDAC cell lines. We demonstrate that Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and that Pin1 inhibition impairs cell viability over time in PDAC cell lines.
Databáze: MEDLINE
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