Reference Detail

Ref Type

Journal Article

PMID

(24623852)

Authors

Smith CC, Lasater EA, Lin KC, Wang Q, McCreery MQ, Stewart WK, Damon LE, Perl AE, Jeschke GR, Sugita M, Carroll M, Kogan SC, Kuriyan J, Shah NP

Title

Crenolanib is a selective type I pan-FLT3 inhibitor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	111	14	2014 Apr 8	5319-24	Proc Natl Acad Sci U S A

URL

Abstract Text

Tyrosine kinase inhibitors (TKIs) represent transformative therapies for several malignancies. Two critical features necessary for maximizing TKI tolerability and response duration are kinase selectivity and invulnerability to resistance-conferring kinase domain (KD) mutations in the intended target. No prior TKI has demonstrated both of these properties. Aiming to maximize selectivity, medicinal chemists have largely sought to create TKIs that bind to an inactive (type II) kinase conformation. Here we demonstrate that the investigational type I TKI crenolanib is a potent inhibitor of Fms tyrosine kinase-3 (FLT3) internal tandem duplication, a validated therapeutic target in human acute myeloid leukemia (AML), as well as all secondary KD mutants previously shown to confer resistance to the first highly active FLT3 TKI quizartinib. Moreover, crenolanib is highly selective for FLT3 relative to the closely related protein tyrosine kinase KIT, demonstrating that simultaneous FLT3/KIT inhibition, a prominent feature of other clinically active FLT3 TKIs, is not required for AML cell cytotoxicity in vitro and may contribute to undesirable toxicity in patients. A saturation mutagenesis screen of FLT3-internal tandem duplication failed to recover any resistant colonies in the presence of a crenolanib concentration well below what has been safely achieved in humans, suggesting that crenolanib has the potential to suppress KD mutation-mediated clinical resistance. Crenolanib represents the first TKI to exhibit both kinase selectivity and invulnerability to resistance-conferring KD mutations, which is unexpected of a type I inhibitor. Crenolanib has significant promise for achieving deep and durable responses in FLT3-mutant AML, and may have a profound impact upon future medicinal chemistry efforts in oncology.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
FLT3	D698N	missense	unknown	FLT3 D698N lies within the protein kinase domain of the Flt3 protein (UniProt.org). D698N has been demonstrated to occur as a secondary resistance mutation in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 25847190, PMID: 24623852), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Apr 2024).	Y
FLT3	N841H	missense	unknown	FLT3 N841H lies within the protein kinase domain of the Flt3 protein (UniProt.org). N841H has been identified in the scientific literature (PMID: 32040554, PMID: 24623852, PMID: 16990784), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Mar 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 D835H	acute myeloid leukemia	sensitive	Crenolanib	Preclinical	Actionable	In a preclinical study, Crenolanib (CP-868596) inhibited Flt3 phosphorylation and induced apoptosis in leukemia cells expressing FLT3 D835H (PMID: 24623852).	24623852