title: Discovery and characterization of novel mutant FLT3 kinase inhibitors.
abstract: For a subpopulation of acute myeloid leukemia (AML) patients, the constitutively activated tyrosine kinase, mutant FLT3, has emerged as a promising target for therapy. The development of drug resistance, however, is a growing concern for mutant FLT3 inhibitors, such as PKC412. Potential therapeutic benefit can arise from the combination of two structurally diverse inhibitors that target-but bind differently to-the same protein or from two inhibitors with completely different mechanisms of action. Thus, there is a need for identification and development of novel FLT3 inhibitors that have the ability to positively combine with PKC412 or standard chemotherapeutic agents used to treat AML as a way to suppress the development of drug resistance and consequently prolong disease remission. Here, we report the effects of the novel type II ATP-competitive inhibitors, HG-7-85-01 and HG-7-86-01, which potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3-ITD or FLT3 kinase domain point mutants via induction of apoptosis and cell cycle inhibition. Antileukemic activity of HG-7-85-01 was shown in vivo to be comparable with that observed with PKC412 in a bioluminescence assay using NCr nude mice harboring Ba/F3-FLT3-ITD-luc+ cells. HG-7-85-01 was also observed to override PKC412 resistance. Finally, HG-7-85-01 and HG-7-86-01 synergized with PKC412 and standard chemotherapeutic agents against mutant PKC412-sensitive and some PKC412-resistant, FLT3-positive cells. Thus, we present a structurally novel class of FLT3 inhibitors that warrants consideration for clinical testing against drug-resistant disease in AML patients.
authors.affiliation: Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ellen_weisberg@dfci.harvard.edu
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Rosemary
authors.initials: R
authors.lastname: Barrett
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.forename: Arghya
authors.initials: A
authors.lastname: Ray
authors.forename: Erik A
authors.initials: EA
authors.lastname: Nelson
authors.forename: Jingrui
authors.initials: J
authors.lastname: Jiang
authors.forename: Daisy
authors.initials: D
authors.lastname: Moreno
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Edward
authors.initials: E
authors.lastname: Fox
authors.forename: Sophia
authors.initials: S
authors.lastname: Adamia
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D051941:fms-Like Tyrosine Kinase 3
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