title: G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia.
abstract: Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.
authors.affiliation: Oscotec Inc., Gyeonggi-do, Republic of Korea;
authors.forename: Hee Kyu
authors.initials: HK
authors.lastname: Lee
authors.forename: Hong Woo
authors.initials: HW
authors.lastname: Kim
authors.forename: In Yong
authors.initials: IY
authors.lastname: Lee
authors.forename: Jungmi
authors.initials: J
authors.lastname: Lee
authors.forename: Jaekyoo
authors.initials: J
authors.lastname: Lee
authors.forename: Dong Sik
authors.initials: DS
authors.lastname: Jung
authors.forename: Sang Yeop
authors.initials: SY
authors.lastname: Lee
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Haejun
authors.initials: H
authors.lastname: Hwang
authors.forename: Jang-Sik
authors.initials: JS
authors.lastname: Choi
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Se Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Jung Keun
authors.initials: JK
authors.lastname: Kim
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Jong Sung
authors.initials: JS
authors.lastname: Koh
authors.forename: Ho-Juhn
authors.initials: HJ
authors.lastname: Song
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D050505:Mutant Proteins / Q000502:physiology; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011728:Pyridones / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: C000588759:G-749 compound; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3