avapritinib   Click here for help

GtoPdb Ligand ID: 10368

Synonyms: Ayvakit® | Ayvakyt® | BLU-285 | BLU285
Approved drug Immunopharmacology Ligand
avapritinib is an approved drug (FDA & EMA (2020))
Compound class: Synthetic organic
Comment: Avapritinib (BLU-285) was developed by Blueprint Medicines as an oral precision therapy to selectively and potently inhibit KIT and PDGFRA mutant kinases [3]. It is a Type I kinase inhibitor that binds the active kinase conformation. Avapritinib binds to the 'switch pocket' of KIT, a domain that regulates the enzyme's catalytic conformation. Compounds that act in this way are often referred to as switch control inhibitors [1]. Another such switch control inhibitor is ripretinib.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 1
Rotatable bonds 5
Topological polar surface area 106.29
Molecular weight 498.24
XLogP 4.21
No. Lipinski's rules broken 0
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Canonical SMILES Fc1ccc(cc1)C(c1cnc(nc1)N1CCN(CC1)c1ncnn2c1cc(c2)c1cnn(c1)C)(N)C
Isomeric SMILES Fc1ccc(cc1)[C@@](c1cnc(nc1)N1CCN(CC1)c1ncnn2c1cc(c2)c1cnn(c1)C)(N)C
InChI InChI=1S/C26H27FN10/c1-26(28,20-3-5-22(27)6-4-20)21-13-29-25(30-14-21)36-9-7-35(8-10-36)24-23-11-18(16-37(23)33-17-31-24)19-12-32-34(2)15-19/h3-6,11-17H,7-10,28H2,1-2H3/t26-/m0/s1
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Summary of Clinical Use Click here for help
In early clinical evaluation avapritinib (BLU-285) demonstrated significant activity in patients with diseases associated with KIT (aggressive systemic mastocytosis (SM) [7] and gastrointestinal stromal tumour (GIST) [6]) and PDGFRA (GIST) activation loop mutations [3,5]. Avapritinib progressed to more advanced clinical evaluation for these indications. Click here to link to ClinicalTrials.gov's full list of avapritinib trials. The developer submitted two New Drug Applications (NDAs) for avapritinib to the FDA; the first for PDGFRA exon 18 mutant GIST (irrespective of prior therapy) and the second as fourth-line therapy for GIST. NDAs for second-line and third-line treatment of GIST will be determined by results from ongoing clinical trials.
Prior to full approval both the EMA and FDA had granted avapritinib orphan designation for the treatment of GIST and mastocytosis. The FDA granted Breakthrough Therapy Designation to avapritinib for two specific forms of these conditions: unresectable or metastatic GIST harbouring the PDGFRA D842V mutation and advanced SM (including aggressive SM and SM with an associated haematologic neoplasm and mast cell leukemia). The first full FDA approval was granted in January 2020, for use in genomically defined unresectable or metastatic PDGFRA exon 18 mutant GIST [2]. Results from NCT03465722, looking at avapritinib vs. regorafenib in heavily pretreated KIT and PDGFRA wild type cancers, indicate non-superiority compared to regorafenib. EMA approval for this indication followed in September 2020.
In June 2021 the FDA approved avapritinib for advanced systemic mastocytosis (AdvSM; including aggressive systemic mastocytosis), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL), based on results from the EXPLORER (NCT02561988) and PATHFINDER (NCT03580655) trials.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT03580655 (PATHFINDER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis Phase 2 Interventional Blueprint Medicines Corporation PATHFINDER trial
NCT02561988 (EXPLORER) Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies Phase 1 Interventional Blueprint Medicines Corporation EXPLORER trial