Multiple myeloma (MM), a kind of plasma cell malignancy, grows preferentially in the bone marrow (BM). Neutrophils serve as the first line of defense against a wide range of pathogens, by utilizing two major mechanisms: phagocytosis and degranulation. Recently, the formation of NETs represents another host defense mechanism of neutrophils against pathogens. Additionally, NETs are formed via a novel cell death pathway called NETosis. In addition, NETs promote cancer-associated thrombosis and have pro-coagulant activity in gastric cancer. The mechanism of NETosis is not entirely understood. However, it has been postulated that citrullination of histones, specifically histone H3, is necessary for chromatin decondensation.
PAD4 is responsible for the citrullination of histone H3 at arginine residues that leads to loss of the positive charge of chromatin and consequently weakens histone-DNA binding facilitating chromatin decondensation during NET formation. To date, several PAD inhibitors activity has been reported. For instance, Clamidine and related compounds represent covalent non-selective irreversible PAD inhibitors. GSK-484, a reversible selective PAD4 inhibitor, blocks calcium ionophore induced NET formation by mouse neutrophils in vitro and through blocking LPS-induced NET generation prevented awakening of dormant cancer cells in an in vivo breast cancer model. Today, I’d like to introduce another PAD4 inhibitor, BMS-P5.
BMS-P5 is a specific and orally active peptidyl arginine deiminase 4 (PAD4) inhibitor. BMS-P5 blocks MM-induced NET formation and delays the progression of MM in a syngeneic mouse model orally active peptidyl arginine deiminase 4 (PAD4) inhibitor.
In vitro, BMS-P5 is also able to inhibit the formation of NETs induced by primary MM cells isolated from the BM of patients with MM. Moreover, in vivo, BMS-P5 with the dose of 50 mg/kg by oral gavage significantly improves the survival of MM-bearing mice. In addition, BMS-P5 may attenuate the presence of pro-tumorigenic proteins in the tumor microenvironment, and thus delay tumor progression.
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