Targeting the protein-protein interaction between IRS1 and mutant p110α for cancer therapy.

摘要: Phosphoinositide-3-kinase, catalytic, alpha polypeptide, which encodes the catalytic p110α subunit of phosphatidylinositol 3-kinase α, is most frequently mutated oncogene in human cancers. Targeting mutant holds great promise for cancer therapy. However, it challenging to develop isoform-specific inhibitors. Most mutations occur at two hot spot regions: an acidic cluster (E542, E545, and Q546) helical domain a histidine residue (H1047) kinase domain. We recently discovered that proteins, but not directly associate with insulin receptor substrate 1 (IRS1). Moreover, we demonstrated disruption protein-protein interaction between IRS1 inhibits growth tumors such mutations. The direct protein mutants may provide more accessible target developing novel precision