Discovery of Small Molecules That Target the Phosphatidylinositol (3,4,5) Trisphosphate (PIP₃)-Dependent Rac Exchanger 1 (P-Rex1) PIP₃-Binding Site and Inhibit P-Rex1-Dependent Functions in Neutrophils.

ABSTRACT: Phosphatidylinositol (3,4,5) trisphosphate (PIP₃)-dependent Rac exchanger 1 (P-Rex1) is a Rho guanine-nucleotide exchange factor that was originally discovered in neutrophils and is regulated by G protein βγ subunits and the lipid PIP₃ in response to chemoattractants. P-Rex1 has also become increasingly recognized for its role in promoting metastasis of breast cancer, prostate cancer, and melanoma. Recent structural, biochemical, and biologic work has shown that binding of PIP₃ to the pleckstrin homology (PH) domain of P-Rex1 is required for its activation in cells. Here, differential scanning fluorimetry was used in a medium-throughput screen to identify six small molecules that interact with the P-Rex1 PH domain and block binding of and activation

SUBMITTER: Cash JN 

PROVIDER: S-EPMC6994817 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature