title: Selective KIT inhibitor KI-328 and HSP90 inhibitor show different potency against the type of KIT mutations recurrently identified in acute myeloid leukemia.
abstract: Activating mutations of KIT play an important role in the pathophysiology of several human malignancies, including acute myeloid leukemia. Activated KIT kinase is therefore a promising molecular target for the treatment of many malignancies harboring KIT activation. Here we examined the potency of a novel KIT inhibitor KI-328 against different types of mutant KIT kinases recurrently identified in AML. KI-328 shows selective potency against KIT kinase for the in vitro kinase assay, and inhibits the growth of wild-type (Wt)- and mutant-KIT-expressing cells, while it has little potency against D816V-KIT. Comparable analysis of several potent KIT inhibitors regarding growth inhibitory effects on a variety of mutant-KIT-expressing cells revealed that multi-kinase inhibitors have the same potency against D816V-KIT as other mutant KITs; however, the predominant potency against D816V-KIT was observed in heat shock protein 90 (HSP90) inhibitors. Furthermore, HSP90 inhibitors suppress the growth of D816V-KIT-expressing cells at the concentration at which the growth of other mutant-KIT-expressing cells is not affected. These results collectively indicated that potent KIT inhibitors have different potency against the type of mutant KIT kinases. Therefore, KIT inhibitors are required to validate potency against several types of mutant KIT kinases for the clinical development.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Tsujimura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Shiotsu
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishida
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D018841:HSP90 Heat-Shock Proteins; C556226:KI 328; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019009:Proto-Oncogene Proteins c-kit