Development of a novel, small molecule inhibitor of RIPK1/3
Standard of care treatments for pancreatic cancer have significant limitations due to the disease’s aggressive nature and late detection. Recently, the development of targeted therapies and immunotherapeutics has shown great efficacy in killing cancer with reduced harm to the patient’s normal cells. The field of cancer immunotherapy works to weaken a tumor’s ability to evade the immune system while simultaneously activating the immune cells to recognize and attack cancer.
In recent years, receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3) have emerged as potential immunotherapeutic targets. These two proteins are integral in the formation of the necrosome, which precipitates the induction of necroptosis, a form of regulated cell death1. Necroptosis results in the release of various chemokines, cytokines, and reactive oxygen species to produce immunosuppressive inflammation in the tumor microenvironment. RIPK1 is highly expressed on tumor-associated macrophages that guard the outside of the tumor, which deactivates immune cells to promote invasion and metastases2. To combat this immunosuppression, the Sharma Lab is developing PRT-2894, a novel, small molecule, dual inhibitor of RIPK1 and RIPK3. PRT-2894 has already demonstrated great potency and bioavailability in previous studies.
Our cell-based assays show PRT-2894’s specificity and on-target potency in pancreatic cancer cell lines. When TNFɑ, a Smac mimetic, and zVad – the three components of TSZ – were added to cancer cells to signal and induce necroptosis, PRT-2894 was able to significantly recover cell viability, and therefore showed direct inhibition of the necroptosis pathway. Western blot analysis of cells dosed with PRT-2894 and then induced with TSZ showed no phosphorylation and therefore no activation of RIPK1 or RIPK3. Organoids formed from pancreatic cancer cells dosed with PRT-2894 also showed greater immune cell infiltration compared to the no treatment control. This demonstrated PRT-2894’s ability to activate the immune system in a 3D model. Further studies will determine PRT-2894’s potential as a clinical candidate to reduce immunosuppressive inflammation and increase immune response to treat pancreatic cancer.