Bomedemstat (IMG-7289) is an orally active, irreversible inhibitor of lysine-specific demethylase 1 (LSD1) that exhibits antineoplastic activities in mouse models of myeloproliferative neoplasms (MPNs), and can be used for research on acute myelogenous leukemia (AML) and myelofibrosis (MF) [1].

Bomedemstat (IMG-7289) selectively inhibits proliferation and induces apoptosis of JAK2 V617F cells by concomitantly increasing expression and methylation of p53, and, independently, the pro-apoptotic factor PUMA and by decreasing the levels of its antiapoptotic antagonist BCL-XL [1]. Bomedemstat (25 nM, 50 nM) and Ruxolitinib (175 nM) synergistically inhibit JAK2 V617F -driven proliferation [1]. Bomedemstat (50 and 100 nM) exerts a pro-apoptotic effect on 3 key regulators of programmed cell death, TP53, BCL-XL, and PUMA [1]. Cell Viability Assay [1] Cell Line: The human cell lines SET-2 (ATCC 608) and HEK293 Concentration: 25 nM, 50 nM Incubation Time: 96 hours Result: 25 nM alone significantly reduced colony formation. Western Blot Analysis [1] Cell Line: SET-2 cells Concentration: 50 and 100 nM Incubation Time: Result: Decreased levels of the antiapoptotic protein BCL-XL and increased levels of the pro-apoptotic protein PUMA.

Once-daily treatment with IMG-7289 normalized or improved blood cell counts, reduced spleen volumes, restored normal splenic architecture, and reduced bone marrow fibrosis. Most importantly, LSD1 inhibition lowered mutant allele burden and improved survival [1]. Animal Model: Mx1cre-Jak2 V617F mice [1] Dosage: 45 mg/kg Administration: Administered daily by oral gavage for either 14, 42, or 56 consecutive days Result: In this Mx-Jak2V617F model of myeloproliferative neoplasm (MPN), mice developed severe splenomegaly (up to 10-fold increase in spleen weight). Splenic architecture was completely destroyed, eliminating demarcation of the white and red pulp. Treatment significantly reduced splenomegaly with a few treated mice normalizing their spleen weight. Remarkably, the 56-day course led to partial restoration of lymph follicles and spleen architecture by histological examination.