8PQK

APO crystal structure of PDGFRA-T674I kinase domain

8PQK の概要

• エントリーDOI: 10.2210/pdb8pqk/pdb
• 分子名称: Platelet-derived growth factor receptor alpha (2 entities in total)
• 機能のキーワード: pdgfra, protein kinase, tyrosine kinase, transmembrane receptor, platelet-derived growth factor, platelet-derived growth factor receptor, gist, gastrointestinal stromal tumors, cancer, gatekeeper mutant, gatekeeper mutation, p16234, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40226.37

構造登録者

Teuber, A.,Mueller, M.P.,Rauh, D. (登録日: 2023-07-11, 公開日: 2023-12-27, 最終更新日: 2024-08-07)

主引用文献

Teuber, A.,Schulz, T.,Fletcher, B.S.,Gontla, R.,Muhlenberg, T.,Zischinsky, M.L.,Niggenaber, J.,Weisner, J.,Kleinbolting, S.B.,Lategahn, J.,Sievers, S.,Muller, M.P.,Bauer, S.,Rauh, D.
Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA.
Nat Commun, 15:63-63, 2024

PubMed 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 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.

PubMed: 38167404
DOI: 10.1038/s41467-023-44376-8

実験手法

X-RAY DIFFRACTION (2 Å)