Project 2

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PIN1 is a cis-trans prolyl isomerase that controls proline-mediated phosphorylation signaling events that is overexpressed both in pancreatic cancer cells and cancer-associated fibroblasts. PIN1 overexpression is a major contributor to tumorigenesis, activating several oncoproteins, including proteins in the KRAS pathway, and simultaneously inactivating several tumor suppressors. Recent studies using genetic and pharmacological inhibitors show that PIN1 regulates key oncogenic pathways. Importantly, PIN1 promotes an immunosuppressive/treatment-resistant TME, by up-regulating PD-L1 (programmed cell-death receptor-1) The chemotherapy drug, gemcitabine, is frequently used in front-line treatment of pancreatic cancer. PIN1 also drives chemotherapy-resistance by degrading the gemcitabine uptake-transporter, ENT1 (equillabrative nuclear transporter-1) both in tumor cells and cancer-associated fibroblasts. Hence, the development of PIN1 inhibitors could increase sensitivity of pancreatic cancer to both chemotherapy and immunotherapy. The laboratory of Dr. Pellecchia (University of California Riverside; UCR) has developed initial PIN1 inhibitors that have promising pharmacokinetic properties. To do this, Dr. Pellecchia used a drug discovery strategy based on a combination of biophysical methods including 1) medicinal chemistry 2) NMR spectroscopy, 3) X-ray crystallography (Dr. Blaha, UCR) and 4) denaturation thermal shift measurements. This structure-based design approach used to derive innovative covalent PIN1 targeting agents that cause degradation of PIN1 in pancreatic cell lines. Guided by our resources and preliminary data, we propose a collaboration between UCR and CoH to 1) optimize and 2) develop a potent and selective PIN1 inhibitor for treatment of pancreatic cancer. Aim 1 will design, synthetize, and iteratively optimize novel, drug-like PIN1 targeting agents. Aim 2 will study the mechanism of action and efficacy of most promising agents in cellular and animal models of pancreatic cancer. We will assess the pharmacokinetics properties (Dr. Horne and CoHCCC shared resources) of refined agents in mice and test their efficacy in animal models of pancreatic cancer (Dr. Horne, Dr. Raoof, CoH) including orthotopic, patient derived xenografts, and transgenic mouse models of pancreatic cancer.