-Author name in bold denotes the presenting author
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2263 EP102: Pharmacological Inhibition of METTL3 Elicits Tumor Growth Inhibition In Vivo

and Demonstrates Synergy with Venetoclax in Various AML Models

Program: Oral and Poster Abstracts
Session: 802. Chemical Biology and Experimental Therapeutics: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Non-Biological therapies, Combination therapy, drug development, Therapies, Pharmacology
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Graeme Fraser1*, Catherine Sorlet2*, Nicolas Parmentier2*, Anne-France Hartiel2*, Sandrine Hospied2*, Clement Mompied2*, Genevieve Absil2*, Killian Oukoloff2* and Guillaume Dutheuil2*

1EPICS SA, Gosselies, AL, Belgium
2EPICS SA, Gosselies, Belgium

METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML)1. EPICS has discovered and optimized a small molecule inhibitor of METTL3 (“M3i”). M3i was shown to inhibit the enzymatic activity of METTL3 (IC50 = 1.8 nM, SPA assay). The anti-proliferative effects of M3i was demonstrated in various AML cell lines (Kasumi, IC50 = 63 nM; MV-411, IC50 = 506 nM; KG1a, IC50 = 99 nM). Biomarkers were evaluated following M3i treatment of Kasumi and MV-411 cells with consistent results demonstrating depletion of oncoproteins relevant to apoptotic (BCL-2, MCL1) and proliferative (MYC, BRD4, SP1) pathways. In addition, combined treatment with M3i and venetoclax showed clear synergistic effects2 to inhibit proliferation on both cell lines consistent with the depletion of BCL-2 and MCL1, known targets for venetoclax activity and resistance mechanisms. M3i has been optimized for oral dosing with oral exposure confirmed in mouse, rat and minipig (oral bioavailability >80%, rat; >30%, minipig). In vivo efficacy was evaluated in a disseminated xenograft model using established systemic MV-411-Luc-mCh-Puro3 in female NSG mice where M3i (10, 30 mg/kg, oral, QDx31 days) demonstrated dose-dependent tumor growth inhibition (p<0.01, relative to vehicle control) of cancer progression as measured by in-life imaging and confirmed by flow cytometry demonstrating significant, dose-dependent pharmacological knockdown of hCD45+ cells in bone marrow, blood and spleen (p<0.01, in all cases). These results confirm that the pharmacological inhibition of METTL3 arrests proliferation of AML and further provide a mechanistic basis for the synergistic activity of M3i in combination with venetoclax as is a viable strategy for the treatment of disease.

1Yankova E et al. (2021), Nature 593:597-601; 2Ianevski A et al. (2022), Nucl Acids Res 50:W739-W743; 3Trachet E (2016), LabCorp Drug Development website: model spotlight MV (4;11)

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH