Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA.

ABSTRACT: Avapritinib is the only potent and selective inhibitor approved for the treatment of D842V-mutant gastrointestinal stromal tumors (GIST), the most common primary mutation of the platelet-derived growth factor receptor α (PDGFRA). The approval was based on the NAVIGATOR trial, which revealed overall response rates of more than 90%. Despite this transformational activity, patients eventually progress, mostly due to acquired resistance mutations or following discontinuation due to neuro-cognitive side effects. These patients have no therapeutic alternative and face a dismal prognosis. Notable, little is known about this drug's binding mode and its medicinal chemistry development, which is instrumental for the development of the next generation of drugs. Against this background, we solve the c

SUBMITTER: Teuber A 

PROVIDER: S-EPMC10761696 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature