Article ; Online: Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA.
2024 Volume 15, Issue 1, Page(s) 63
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 ... ...
| 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. |
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| MeSH term(s) | Humans ; Receptor, Platelet-Derived Growth Factor alpha/genetics ; Receptor, Platelet-Derived Growth Factor alpha/metabolism ; Gastrointestinal Stromal Tumors/drug therapy ; Gastrointestinal Stromal Tumors/genetics ; Gastrointestinal Stromal Tumors/pathology ; Pyrazoles/therapeutic use ; Pyrroles/pharmacology ; Pyrroles/therapeutic use ; Mutation ; Proto-Oncogene Proteins c-kit/genetics ; Antineoplastic Agents/pharmacology |
| Chemical Substances | avapritinib (513P80B4YJ) ; Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1) ; Pyrazoles ; Pyrroles ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1) ; Antineoplastic Agents |
| Language | English |
| Publishing date | 2024-01-02 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 2553671-0 |
| ISSN | 2041-1723 ; 2041-1723 |
| ISSN (online) | 2041-1723 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-023-44376-8 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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