G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia

• Published in: Blood 2014-04, Vol.123 (14), p.2209-2219
• Main Authors: Lee, Hee Kyu, Kim, Hong Woo, Lee, In Yong, Lee, Jungmi, Lee, Jaekyoo, Jung, Dong Sik, Lee, Sang Yeop, Park, Sung Ho, Hwang, Haejun, Choi, Jang-Sik, Kim, Jung-Ho, Kim, Se Won, Kim, Jung Keun, Cools, Jan, Koh, Jong Sung, Song, Ho-Juhn
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug Synergism; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - chemistry; fms-Like Tyrosine Kinase 3 - genetics; Humans; K562 Cells; Leukemia, Myeloid, Acute - drug therapy; Mice; Mutant Proteins - physiology; Mutation, Missense; Myeloid Neoplasia; Protein Kinase Inhibitors - therapeutic use; Protein Structure, Tertiary - genetics; Pyridones - therapeutic use; Pyrimidines - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-04-493916

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. •A novel inhibitor G-749 is very potent against FLT3 kinase mutants including D835Y and ITD/F691L that confer resistance to PKC412 and AC220.•G-749 shows several desirable characteristics to overcome other drug resistances conferred by patient plasma, FLT3 ligand, and stromal cells.