title: Crenolanib is a selective type I pan-FLT3 inhibitor.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, and Division of Laboratory Medicine, University of California, San Francisco, CA 94143.
authors.forename: Catherine Choy
authors.initials: CC
authors.lastname: Smith
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Lasater
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Lin
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Melissa Quino
authors.initials: MQ
authors.lastname: McCreery
authors.forename: Whitney K
authors.initials: WK
authors.lastname: Stewart
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Damon
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Perl
authors.forename: Grace R
authors.initials: GR
authors.lastname: Jeschke
authors.forename: Mayumi
authors.initials: M
authors.lastname: Sugita
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D010880:Piperidines; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C577197:crenolanib
keywords: D835 mutations; activation-loop mutations; sorafenib