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Activation of Wnt/β-catenin signaling is associated with pancreatic and colorectal cancer, among others. To-date, there are no FDA-approved small molecule Wnt/β-catenin inhibitors and many past efforts resulted in compounds with undesirable off-target effects. We recently identified a series of benzimidazole analogs as potent inhibitors of Wnt/β-catenin signaling. Here, we show that the lead compound SRI36160 displayed selective Wnt inhibition and potent antiproliferative activity in pancreatic and colorectal cancer cells. Moreover, SRI36160 had no effect on STAT3 and mTORC1 signaling in pancreatic and colorectal cancer cells, and was not effective in inhibiting proliferation of non-cancerous cells. Our findings suggest that this series of benzimidazole analogs presents a novel approach for the treatment of Wnt-dependent cancers such as colorectal and pancreatic cancer.

Activation of Wnt/β-catenin signaling is associated with pancreatic and colorectal cancer, among others. To-date, there are no FDA-approved small molecule Wnt/β-catenin inhibitors and many past efforts resulted in compounds with undesirable off-target effects. We recently identified a series of benzimidazole analogs as potent inhibitors of Wnt/β-catenin signaling. Here, we show that the lead compound SRI36160 displayed selective Wnt inhibition and potent antiproliferative activity in pancreatic and colorectal cancer cells. Moreover, SRI36160 had no effect on STAT3 and mTORC1 signaling in pancreatic and colorectal cancer cells, and was not effective in inhibiting proliferation of non-cancerous cells. Our findings suggest that this series of benzimidazole analogs presents a novel approach for the treatment of Wnt-dependent cancers such as colorectal and pancreatic cancer.

We report here the rational design and validation of a peptide inhibitor to the PD-1/PD-L1 interaction as an attempt to develop a viable alternative to current inhibitory antibodies. We demonstrated, by biolayer interferometry and in silico docking simulations, that a PD-L1 peptide mimetic (PL120131) can interfere with the PD-1/PD-L1 interaction by binding to PD-1. We show that PL120131 is capable of inhibiting PD-1 mediated apoptotic signaling pathway and rescuing Jurkat cells and primary lymphocytes from apoptosis. Additionally, we show that PL120131 treatment allows for CTL anti-tumor activity. Furthermore, PL120131 can maintain co-culture survivability and activity of T Cells in a 3D co-culture model better than the anti-PD-1 blocking antibody. Together, the characterization of this PD-1/PD-L1 inhibiting peptide provides insight regarding the ability to inhibit PD-L1 binding while maintaining CTL viability and activity that can further the development of alternatives to antibody based immunotherapies.