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

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 crystal structures of avapritinib in complex with wild-type and mutant PDGFRA and stem cell factor receptor (KIT), which provide evidence and understanding of inhibitor binding and lead to the identification of a sub-pocket (Gα-pocket). We utilize this information to design, synthesize and characterize avapritinib derivatives for the determination of key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration.

[Rectal localisation of carcinoid tumour by radiography (author's transl)]. / Tumeur carcinoïde de localisation rectale de découverte radiologique.

Carcinoid tumors of the rectum are rare and their radiologic visualization is exceptional. In the series we report about an incidental finding during double contrast enema which takes the form of an expanding tumor developing inside the intestinal lumen and showing no signs of malignity. Standard investigation in the follow up of rectal carcinoid tumors showed no hepatic mestastisis, no other foci in the digestive tract and no biologic anomalies. The patient did not complain of carcinoid syndrome. Double contrast enema is the only process enabling the discovery of rectal masses so small with non negligible frequency (2% of our explorations). Whatever the radiologic aspect and localization, fibroscopic and histologic examinations are necessary in order to make an accurate diagnosis of their nature.