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|Ref Type||Journal Article|
|Authors||Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, Levis M|
|Title||Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants.|
|Date||2014 Jan 2|
|Abstract Text||Mutations of the type III receptor tyrosine kinase FLT3 occur in approximately 30% of acute myeloid leukemia patients and lead to constitutive activation. This has made FLT3-activating mutations an attractive drug target because they are probable driver mutations of this disease. As more potent FLT3 inhibitors are developed, a predictable development of resistance-conferring point mutations, commonly at residue D835, has been observed. Crenolanib is a highly selective and potent FLT3 tyrosine kinase inhibitor (TKI) with activity against the internal tandem duplication (FLT3/ITD) mutants and the FLT3/D835 point mutants. We tested crenolanib against a panel of D835 mutant cell lines and primary patient blasts and observed superior cytotoxic effects when compared with other available FLT3 TKIs such as quizartinib and sorafenib. Another potential advantage of crenolanib is its reduced inhibition of c-Kit compared with quizartinib. In progenitor cell assays, crenolanib was less disruptive of erythroid colony growth, which may result in relatively less myelosuppression than quizartinib. Finally, correlative data from an ongoing clinical trial demonstrate that acute myeloid leukemia patients can achieve sufficient levels of crenolanib to inhibit both FLT3/ITD and resistance-conferring FLT3/D835 mutants in vivo. Crenolanib is thus an important next-generation FLT3 TKI.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Crenolanib||CP-868596|CP-868,596||FLT3 Inhibitor 54 PDGFR Inhibitor (Pan) 27||Crenolanib (CP-868596) is a type III receptor tyrosine kinase inhibitor of PDGFR-alpha/beta and FLT3, which results in inhibition of downstream signaling and prevents growth in tumor cells (PMID: 22745105, PMID: 24227820, PMID: 29137311, PMID: 31309543).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|FLT3||D835F||missense||unknown||FLT3 D835F lies within the activation loop in the protein kinase domain of the Flt3 protein (PMID: 25837374). D835F has been associated with acquired resistance to sorafenib (PMID: 24227820), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Mar 2020).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FLT3 exon 14 ins FLT3 D835F||acute myeloid leukemia||predicted - resistant||Sorafenib||Case Reports/Case Series||Actionable||In a clinical case study, FLT3 D835F was identified as an acquired resistance mutation in a patient with acute myeloid leukemia harboring a FLT3 internal tandem duplication (ITD) whose disease progressed on Nexavar (sorafenib) after initial response (PMID: 24227820).||24227820|
|FLT3 exon 14 ins FLT3 D835F||acute myeloid leukemia||predicted - sensitive||Crenolanib||Preclinical - Patient cell culture||Actionable||In a preclinical study, Crenolanib inhibited growth of blasts derived from a patient with acute myeloid leukemia harboring FLT3 internal tandem duplication (ITD) and FLT3 D835F (PMID: 24227820).||24227820|