A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations

• Published in: Blood Vol. 131; no. 4; pp. 426 - 438
• Main Authors: Yamaura, Takeshi, Nakatani, Toshiyuki, Uda, Ken, Ogura, Hayato, Shin, Wigyon, Kurokawa, Naoya, Saito, Koichi, Fujikawa, Norie, Date, Tomomi, Takasaki, Masaru, Terada, Daisuke, Hirai, Atsushi, Akashi, Akimi, Chen, Fangli, Adachi, Yoshiya, Ishikawa, Yuichi, Hayakawa, Fumihiko, Hagiwara, Shinji, Naoe, Tomoki, Kiyoi, Hitoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.01.2018
• Subjects: Amides - pharmacokinetics; Amides - pharmacology; Amides - therapeutic use; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - chemistry; fms-Like Tyrosine Kinase 3 - genetics; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Mice; Molecular Docking Simulation; Mutation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Pyrimidines - therapeutic use
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-05-786657

An activating mutation of Fms-like tyrosine kinase 3 (FLT3) is the most frequent genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although many FLT3 inhibitors have been clinically developed, no first-generation inhibitors have demonstrated clinical efficacy by monotherapy, due to poor pharmacokinetics or unfavorable safety profiles possibly associated with low selectivity against FLT3 kinase. Recently, a selective FLT3 inhibitor, quizartinib, demonstrated favorable outcomes in clinical studies. However, several resistant mutations emerged during the disease progression. To overcome these problems, we developed a novel FLT3 inhibitor, FF-10101, designed to possess selective and irreversible FLT3 inhibition. The co-crystal structure of FLT3 protein bound to FF-10101 revealed the formation of a covalent bond between FF-10101 and the cysteine residue at 695 of FLT3. The unique binding brought high selectivity and inhibitory activity against FLT3 kinase. FF-10101 showed potent growth inhibitory effects on human AML cell lines harboring FLT3 internal tandem duplication (FLT3-ITD), MOLM-13, MOLM-14, and MV4-11, and all tested types of mutant FLT3-expressing 32D cells including quizartinib-resistant mutations at D835, Y842, and F691 residues in the FLT3 kinase domain. In mouse subcutaneous implantation models, orally administered FF-10101 showed significant growth inhibitory effect on FLT3-ITD-D835Y- and FLT3-ITD-F691L–expressing 32D cells. Furthermore, FF-10101 potently inhibited growth of primary AML cells harboring either FLT3-ITD or FLT3-D835 mutation in vitro and in vivo. These results indicate that FF-10101 is a promising agent for the treatment of patients with AML with FLT3 mutations, including the activation loop mutations clinically identified as quizartinib-resistant mutations. •FF-10101 has selective and potent inhibitory activities against FLT3 by forming a covalent bond to the C695 residue.•FF-10101 shows high efficacy against AML cells with FLT3 mutations including quizartinib-resistant activation loop mutations.