Bomedemstat: Pre-clinical and Clinical Data
Bomedemstat was investigated in multiple mouse models of myeloproliferative neoplasms using the same mutant alleles found in patients with MPNs (MplW515L, Jak2V617F).
In a Jak2V617F mouse model of an MPN, bomedemstat reduced spleen sizes, lowered WBCs and platelet counts, reduced inflammatory cytokines and mutant cell burdens, facilitated resorption of reticulin fibrosis in bone marrow and enhanced survival.
The regulation of gene expression includes the modification of the histone proteins that bundle DNA. Histone-DNA complexes are assembled into regions that are either too tightly wound to be accessible to transcription factors or in an “open” state poised for transcription. A variety of enzymes chemically modify histones to alter their transcriptional potential. LSD1 (also known as KDM1A) is an enzyme that removes methyl groups from histone 3 lysine 4 (H3K4). The methyl marks on H3K4 are associated with active transcription and the demethylase activity of LSD1 is, hence, generally though not exclusively associated with the repression of transcription. In the bone marrow, LSD1 is active as cells transit through differentiation and gene expression programs that characterize each step. Genes are successively silenced as cells reach their final stage of maturity. LSD1 activity, however, is required for the high level of expression of inflammatory cytokines in JAK-STAT activated cells, mostly commonly found in the myeloproliferative disorders.