Reference Detail

Ref Type

Abstract

PMID

Authors

Brian Law, Tripta Rughwani, Tenley C. Archer, Lekha Kumar, Daniel Lu, Priyanka Somanath, Yan Ma, Xiaodong Wang, David Sperandio, Steve Morris, Thorsten Kirschberg, Mini Balakrishnan, Thomas Butler

Title

Bmf-500: An Orally Bioavailable Covalent Inhibitor of FLT3 with High Selectivity and Potent Antileukemic Activity in FLT3-Mutated AML

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	140	Supplement 1	November 15, 2022

URL

https://ashpublications.org/blood/article/140/Supplement%201/6191/487213/Bmf-500-An-Orally-Bioavailable-Covalent-Inhibitor

Abstract Text

Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) are the most frequent genetic alteration in AML and are associated with poor prognosis. Though several FLT3 inhibitors have entered clinical trials and reached commercialization, adverse events and dose-limiting toxicities often restrict the therapeutic window and limit their long-term use. Such limitations impact the ability to achieve long-lasting response in patients and ultimately result in therapy-induced resistance. Exquisite potency combined with high selectivity and improved safety profile is expected to help improve tolerance and overall treatment outcomes of FLT3-targeted therapy. BMF-500 was designed as a highly potent and selective, covalent, small molecule inhibitor of FLT3, that binds irreversibly to a reactive cysteine in the kinase active site. BMF-500 is a picomolar inhibitor with markedly improved potency over gilteritinib, a reversible inhibitor of FLT3. BMF-500 selectively killed AML cells harboring FLT3 activating mutations, including MV4-11 and MOLM-13, and engineered cells expressing FLT3 internal tandem duplications (FLT3-ITD) and/or FLT3 tyrosine kinase domain (TKD) mutations. In ex vivo cultures, BMF-500 as a single agent induced potent growth inhibition of patient-derived AML cells harboring either FLT3-ITD or FLT3 non-ITD mutations. The potent covalent inhibition of FLT3 by BMF-500 manifested in effective and durable cellular response that was improved over gilteritinib. For example, a 3-hour exposure followed by wash-out of BMF-500 outperformed 4 days of continuous exposure to gilteritinib, at all concentrations tested. In cells harboring FLT3 activating mutations, BMF-500 induced dose-dependent inhibition of FLT3 phosphorylation and downstream signaling, including phospho-STAT5 and phospho-ERK. A 1-hour pulse treatment with BMF-500 was sufficient to achieve deep and durable target inhibition for greater than 24 hours, an effect not observed with gilteritinib under similar conditions. Profiling BMF-500 across a broad panel of kinases and key cell-surface receptors revealed high selectivity for FLT3 mutants and selectivity against cKit. Potent FLT3 inhibition and high selectivity of BMF-500 translated to sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML. Orally administered BMF-500 was well tolerated over 4 weeks of dosing. Study results including efficacy and PD response will be presented. Collectively these data demonstrate BMF-500 to be a novel FLT3 inhibitor with best-in-class potential, given its efficacy, durability, and selectivity in comparison to existing FLT3 inhibitors.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
BMF-500	BMF-500	2	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BMF-500		BMF500\|BMF 500	FLT3 Inhibitor 69	BMF-500 is a covalent FLT3 inhibitor, which reduces downstream signaling and potentially decreases tumor growth (Blood (2022) 140 (Supplement 1): 6191-6192).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 act mut	acute myeloid leukemia	predicted - sensitive	BMF-500	Preclinical	Actionable	In a preclinical study, BMF-500 inhibited Flt3 phosphorylation and downstream signaling and decreased viability of acute myeloid leukemia cell lines harboring FLT3 activating mutations in culture and induced tumor regression and improved survival in xenograft models (Blood (2022) 140 (Supplement 1): 6191-6192).	detail...
FLT3 exon 14 ins	acute myeloid leukemia	predicted - sensitive	BMF-500	Preclinical - Patient cell culture	Actionable	In a preclinical study, BMF-500 decreased viability of patient-derived acute myeloid leukemia cells harboring a FLT3-ITD mutation in culture (Blood (2022) 140 (Supplement 1): 6191-6192).	detail...