An SH3-binding allosteric modulator stabilizes the global conformation of the AML-associated Src-family kinase, Hck.

ABSTRACT: While ATP-site inhibitors for protein-tyrosine kinases are often effective drugs, their clinical utility can be limited by off-target activity and acquired resistance mutations due to the conserved nature of the ATP-binding site. However, combining ATP-site and allosteric kinase inhibitors can overcome these shortcomings in a double-drugging framework. Here we explored the allosteric effects of two pyrimidine diamines, PDA1 and PDA2, on the conformational dynamics and activity of the Src-family tyrosine kinase Hck, a promising drug target for acute myeloid leukemia. Using ¹H-¹⁵N HSQC NMR, we mapped the binding site for both analogs to the SH3 domain. Despite the shared binding site, PDA1 and PDA2 had opposing effects on near-full-length Hck dynamics by hydrogen-deuter

SUBMITTER: Selzer AM 

PROVIDER: S-EPMC11786751 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature