A Novel Selective Inhibitor JBI-589 Targets PAD4-Mediated Neutrophil Migration to Suppress Tumor Progression

Abstract

Neutrophils are closely involved in the regulation of tumor progression and formation of pre-metastatic niches. However, the mechanisms of their involvement and therapeutic regulation of these processes remain elusive. Here, we report a critical role of neutrophil peptidylarginine deiminase 4 (PAD4) in neutrophil migration in cancer. In several transplantable and genetically engineered mouse models, tumor growth was accompanied by significantly elevated enzymatic activity of neutrophil PAD4. Targeted deletion of PAD4 in neutrophils markedly decreased the intratumoral abundance of neutrophils and led to delayed growth of primary tumors and dramatically reduced lung metastases. PAD4 mediated neutrophil accumulation by regulating the expression of the major chemokine receptor CXCR2. PAD4 expression and activity as well as CXCR2 expression were significantly upregulated in neutrophils from patients with lung and colon cancers compared to healthy donors, and PAD4 and CXCR2 expression were positively correlated in neutrophils from cancer patients. In tumor-bearing mice, pharmacological inhibition of PAD4 with the novel PAD4 isoform-selective small molecule inhibitor JBI-589 resulted in reduced CXCR2 expression and blocked neutrophil chemotaxis. In mouse tumor models, targeted deletion of PAD4 in neutrophils or pharmacological inhibition of PAD4 with JBI-589 reduced both primary tumor growth and lung metastases and substantially enhanced the effect of immune checkpoint inhibitors. Taken together, these results suggest a therapeutic potential of targeting PAD4 in cancer.

The coming of age of neutrophil extracellular traps in thrombosis: Where are we now and where are we headed?

“…The development of PAD4 inhibitors has continued based on the GSK484 base structure with drugs with oral availability. Compound BMS‐P5 was reported to have efficacy in delaying multiple myeloma progression 234 and the lead candidate JBI‐589 shows efficacy in NET‐mediated sequelae of solid tumors, 235 supporting previous data showing similar protection with PAD4 deficiency in mice 236 . Cancer‐associated thrombosis and metastasis, for which we recently reviewed the implications of NET release, 237,238 indeed represent promising clinical targets for NET inhibition.…”

The role of protein arginine deiminase 4-dependent neutrophil extracellular traps formation in ulcerative colitis

“…Studies in other systems have shown that various modalities such as PADs inhibitors ( 21 , 36 , 37 ), DNA-degrading DNases ( 4 ), and SNase ( 11 ) can reduce the level of NETs in vivo . Cl-amidine is an effective, small molecular inhibitor of PADs.…”

Protein citrullination: inhibition, identification and insertion

“…Notably, however, the decrease in disease severity was less than that observed for BB-Cl-amidine suggesting the possibility that additional isozymes played a role in disease. Several more advanced PAD4 selective inhibitors based on the GSK484 scaffold have been developed including BMS-P5 [53] and JBI-589 (figure 2 c ) [54]. Notably, BMS-P5 efficiently blocks NETosis and improves survival in a murine model of multiple myeloma [53].…”