5X02

Crystal structure of the FLT3 kinase domain bound to the inhibitor FF-10101

Summary for 5X02

• Entry DOI: 10.2210/pdb5x02/pdb
• Descriptor: Receptor-type tyrosine-protein kinase FLT3, N-[(2S)-1-[5-[2-[(4-cyanophenyl)amino]-4-(propylamino)pyrimidin-5-yl]pent-4-ynylamino]-1-oxidanylidene-propan-2-yl]-4-(dimethylamino)-N-methyl-but-2-enamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: tyrosine kinase, transferase, irreversible inhibitor complex, kinase catalytic domain, transferase-transferase inihibitor complex, transferase/transferase inihibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 40829.40

Authors

Fujikawa, N.,Hirano, D.,Takasaki, M.,Terada, D.,Hagiwara, S.,Park, S.-Y.,Sugiyama, K. (deposition date: 2017-01-19, release date: 2018-01-24, Last modification date: 2024-11-20)

Primary citation

Yamaura, T.,Nakatani, T.,Uda, K.,Ogura, H.,Shin, W.,Kurokawa, N.,Saito, K.,Fujikawa, N.,Date, T.,Takasaki, M.,Terada, D.,Hirai, A.,Akashi, A.,Chen, F.,Adachi, Y.,Ishikawa, Y.,Hayakawa, F.,Hagiwara, S.,Naoe, T.,Kiyoi, H.
A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells withFLT3mutations.
Blood, 131:426-438, 2018

PubMed Abstract: An activating mutation of () 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 internal tandem duplication (-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 -ITD or -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 mutations, including the activation loop mutations clinically identified as quizartinib-resistant mutations.

PubMed: 29187377
DOI: 10.1182/blood-2017-05-786657

Experimental method

X-RAY DIFFRACTION (2.401 Å)