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https://www.selleckchem.com/products/ipi-549.html Pancreatic cancer is characterized by an extensive and complex microenvironment, and is resistant to both chemotherapy and immune checkpoint blockade. The study by Principe and colleagues in this issue of Cancer Research proposes a combinatorial approach based on targeting the very mechanisms of resistance to gemcitabine, a commonly used chemotherapeutic agent. The authors show that gemcitabine treatment causes profound changes in the pancreatic cancer microenvironment, including elevated TGFβ signaling and immune checkpoint expression, as well as increased antigen presentation in tumor cells. Accordingly, they show that the combination of chemotherapy, TGFβ signaling inhibition, and immune checkpoint blockade effectively restores antitumor immunity and results in a significant survival benefit.See related article by Principe et al., p. 3101.The ADP-ribosylhydrolase ARH3 plays a key role in DNA damage repair, digesting poly(ADP-ribose) and removing ADP-ribose from serine residues of the substrates. Specific inhibitors that selectively target ARH3 would be a useful tool to examine DNA damage repair, as well as a possible strategy for tumor suppression. However, efforts to date have not identified any suitable compounds. Here, we used in silico and biochemistry screening to search for ARH3 inhibitors. We discovered a small molecule compound named ARH3 inhibitor 26 (AI26) as, to our knowledge, the first ARH3 inhibitor. AI26 binds to the catalytic pocket of ARH3 and inhibits the enzymatic activity of ARH3 with an estimated IC50 of ∼2.41 μm in vitro Moreover, hydrolysis of DNA damage-induced ADP-ribosylation was clearly inhibited when cells were pretreated with AI26, leading to defects in DNA damage repair. In addition, tumor cells with DNA damage repair defects were hypersensitive to AI26 treatment, as well as combinations of AI26 and other DNA-damaging agents such as camptothecin and doxorubicin. Collectively, these res

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