Targeting FLT3-ITD Mutations: Unveiling a Potent Inhibitor for AML Therapy

Acute myeloid leukemia (AML) is a prevalent and life-threatening condition for adults, where the FLT3 kinase mutation, particularly the internal tandem duplication (FLT3-ITD), is identified in approximately 30% of cases and represents a significant drug target. Several FLT3 inhibitors are in clinical trials, with PKC412 being recognized by the FDA for its breakthrough therapy in treating FLT3-ITD positive AML.

Preclinical studies have indicated that the myelosuppression toxicity of certain FLT3 inhibitors could be attributed to off-target effects, such as the inhibition of c-KIT. A new compound, CHMFL-FLT3-165, has been developed with high potency and selectivity against FLT3 kinase, showing significant inhibitory effects on FLT3-ITD positive AML cell lines and patient cells, with reduced leukemia growth in preclinical models.

CHMFL-FLT3-165, also known as 'compound 165,' has demonstrated an IC50 of 12 and 4 nM against FLT3 wild-type and FLT3-ITD kinases, respectively, and has been identified as an ATP competitive inhibitor with a typical type I binding conformation in FLT3 kinase. It shows high potency and selectivity against engineered FLT3 expressing cell lines, with a 7000-fold selectivity advantage over the parental cell line.

The compound has also shown inhibitory activity against other oncogenic FLT3 mutations and drug-resistant mutations, albeit with slightly reduced potency. It has induced significant anti-proliferation effects in FLT3-ITD AML cancer cell lines, with minimal activity against FLT3 wild-type expressing cell lines, suggesting a favorable safety profile.

Compound 165 has been tested for its selectivity and has shown binding affinity against several kinases, but with a good selectivity score. It has also been shown to effectively inhibit FLT3 auto-phosphorylation in cancer cell lines and primary cells, suppressing downstream signaling pathways and inducing apoptosis.

In vivo studies have demonstrated dose-dependent tumor inhibition and significant reduction of tumor cells in various tissues without apparent toxicity. The compound has also been shown to have a safety window, as it does not affect bone marrow proliferation at certain concentrations.

Overall, CHMFL-FLT3-165 is a promising FLT3 kinase inhibitor with strong biochemical inhibition, potent anti-proliferation effects, and significant in vivo tumor suppression. It may offer less adverse effects compared to currently approved FLT3 inhibitors due to its selectivity and could be advantageous in treating drug-resistant FLT3 mutations. Further preclinical safety evaluations are underway.