Human Kinase IGF1R/IR Inhibitor Linsitinib Controls the In Vitro and Intracellular Growth of Mycobacterium tuberculosis.

ABSTRACT: ATP provides energy in the biosynthesis of cellular metabolites as well as regulates protein functions through phosphorylation. Many ATP-dependent enzymes are antibacterial and anticancer targets including human kinases acted on by most of the successful drugs. In search of new chemotherapeutics for tuberculosis (TB), we screened repurposing compounds against the essential glutamine synthase (GlnA1) of Mycobacterium tuberculosis (Mtb) and identified linsitinib, a clinical-stage drug originally targeting kinase IGF1R/IR as a potent GlnA1 inhibitor. Linsitinib has direct antimycobacterial activity. Biochemical, molecular modeling, and target engagement analyses revealed the inhibition is ATP-competitive and specific in Mtb. Linsitinib also improves autophagy flux in both Mtb-infected

SUBMITTER: Wang H 

PROVIDER: S-EPMC11807261 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature