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

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.

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

“…In contrast, because many type I inhibitors are designed to bind to only the ATP‐binding site, they can bind to the active conformation of FLT3; however, they have more broad‐kinase inhibitory activities than type II inhibitors, due to the similarity of binding sites among kinases. To resolve these problems, we developed a novel FLT3 inhibitor, FF‐10101, in collaboration with FUJIFILM (Kanagawa, Japan), which was designed to form a covalent binding between the C695 residue of FLT3 (Figure ).yyyy This covalent bond formation of FF‐10101 induces irreversible inhibition of FLT3 and potent and selective inhibitory activity, and maintains the binding ability both to the active and inactive conformations of FLT3. The unique binding of FF‐10101 also provides broad and potent inhibitory effects on various FLT3 mutations, including the gatekeeper mutation F691L.…”

Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo

“…However, inhibitor resistance, largely though acquired mutations in the Flt3 kinase domain, has limited their clinical utility 8 . Compounds that inhibit common Flt3 resistance mutants have also been developed and are in clinical trials, such as FF-10101 9 and PLX3397 10 .…”

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

“…FLT3/ITD and FLT3/TKD are ideal targets for small molecule inhibitors. Multiple FLT3 inhibitors are in clinical development, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101 [22][23][24][25][26][27][28][29][30]. Midostaurin and gilteritinib have been approved by FDA for Flt3 mutated AML [31].…”