GSK547, a Mono-Selective RIPK1 Inhibitor, drives Macrophage-Mediated Th1/Th17 and CTL Activation

RIPK1 (receptor-interacting serine/threonine protein kinase 1) belongs to the receptor interacting protein kinases family, which contains seven members. RIPK1 plays a vital role in cell survival and cell death. It involves in apoptosis and necroptosis.

Pancreatic ductal adenocarcinoma (PDA) is the most common pancreatic cancer. It is characterized by immune tolerance. However, tumor-associated macrophages express high levels of RIPK1 in PDA.

Thus, inhibition of RIPK1 has the potential in the treatment of PDA via macrophages.

In the beginning, researchers proved RIPK1 is a potential target in PDA. So they carried out a series of experiments to find out the potential compound. Consequently, they discovered GSK547 (RIP1i; GSK’547) as the promising one.

GSK547 is a potent and highly selective of RIPK1, due to binding in the allosteric pocket between the N-terminal and C-terminal domains at the back of the ATP binding site.

Besides, GSK547 acts on T Cells. It elevates pan-T cell infiltration. It also significantly activates PDA-infiltrating T cells. Furthermore, the inhibitor enhances Th1/Th17 differentiation of CD4+ T cells and cytotoxic CD8+ T cell activation in PDA.

Moreover, GSK547 inhibition is T cell dependent, and causes immunogenic reprogramming of intra-tumoral macrophages.

In addition, GSK547 exhibits potent effect in vivo. GSK547 inhibits tumor growth and prolongs the survival in mice. It displays protective activity against PDA.

Totally, GSK547 is a highly selective RIPK1 inhibitor, acts on inflammatory cells and is protective against PDA.

1. Wang W, et al. Cancer Cell. 2018 Nov 12;34(5):757-774.e7.