Biomea Fusion, Inc. Publishes Abstract on BMF-219 at ASH Annual Meeting
November 04, 2021 at 08:19 pm IST
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Biomea Fusion, Inc. announced that an abstract containing preclinical data for BMF-219 has been published in Blood, the journal of the American Society of Hematology. The study, as published in Blood, analyzed how Biomea?s irreversible menin inhibitor, BMF-219, is impacting acute myeloid leukemia cells against the background of transcription factors in the GEO dataset. Menin is involved in many protein-protein interactions as part of a larger complex, with Menin and MLL/KMT2A being an example of one of those interactions. Here we investigated how ?219 disrupts menin globally (selective disruption of global menin co-factors in addition to KMT2A). The study demonstrates further the ability of BMF-219 to modulate MYC expression in leukemia cells, offering the foundation for exploring its activity in DLBCL cells. Transcription factor (TF) activity inference was calculated by analysis of TF-binding sites established by chromatin immunoprecipitation sequencing (ChIP-seq) GEO datasets that overlap with BMF-219 mediated differentially expressed genes in MOLM-13 cells using a published statistical framework and algorithm. This analysis revealed MYC, and its co-factor MAX, as top TFs regulating this subset of differentially expressed genes by BMF-219, as TF activity inference was highly enriched for both proteins. Established menin co-factors (KMT2A, JUND) also emerged as top candidates in this dataset. These results strongly point toward altered MYC-activity mediated by BMF-219 in leukemia cells, prompting additional exploration in MYC-dependent lymphoid malignancies. Transcription factor (TF) activity inference using ChIP-seq of differentially expressed genes in MOLM-13 cells incubated with 500 nM BMF-219 at 24 hours. Each bar represents a study in the GEO repository using the specified TF antibody. TFs with more than one bar represent multiple study sets in GEO that overlap with BMF-219 mediated differentially expressed genes. MYC and MAX are top TFs regulating this subset of differentially expressed genes (p=10-49.5). Established menin co-factors (KMT2A, JUND) also emerged as top candidates in this dataset.? Using these results as the basis for further investigation, we explored BMF-219 and menin reversible inhibitors? impact on cell viability in two different DLBCL double hit lymphoma (DHL) cell lines (DB and Toledo). Single-agent BMF-219 reduced >90% of cell viability in DB and Toledo cells, at 1.0?M and 0.36 ?M, respectively. The IC50 values of BMF-219 were calculated near 0.3 mM for both DB and Toledo cells; however, the two reversible menin inhibitors tested were significantly less effective. One of the reversible inhibitors exhibited IC50 values at multi-fold higher drug concentrations than BMF-219 in both cell lines tested and the other reversible compound tested did not show sensitivity to either cell line.
Biomea Fusion, Inc. is a clinical-stage biopharmaceutical company. The Company is focused on the discovery and development of oral covalent small molecules to treat patients with metabolic diseases and genetically defined cancers. A covalent small molecule is a synthetic compound that forms a permanent bond to its target protein. The Company is utilizing its proprietary FUSION System to discover, design and develop a pipeline of covalent-binding small molecule medicines designed to maximize clinical benefit for patients. Its lead product candidate, BMF-219, is designed to be an oral, potent, and selective covalent inhibitor of menin, built from its FUSION System. It is developing BMF-219 for the treatment of menin regulated or dependent diseases, such as type 1 and type 2 diabetes as well as subtypes of liquid and solid tumors. Its second development candidate, BMF-500, a covalent inhibitor of activating mutations of the FMS-like tyrosine kinase 3 (FLT3).