With the advent of checkpoint inhibitors (CI), immunotherapies have revolutionized the field of oncology and the ways in which malignancies are treated. Many of the CIs on the market today function by preventing the ligation of immunosuppressive receptors on a subset of lymphocytes known as T cells. As such, T cells that infiltrate the tumor microenvironment (TME) are able to elicit cytotoxic effects, resulting in a rapid reduction in tumor burden. Patients responding to CI therapies experience increased survival rates, however, the number of non-responding patients, or patients who develop resistance, is unacceptably high. One mechanism contributed to lack of CI response is associated with the metabolic collapse experienced by tumor infiltrating lymphocytes (TIL). As tumor cells rely on a Warburg metabolism, the TME is devoid of nutrients and presents a barren and oftentimes hypoxic environment for TIL. Deprived of the essential factors for cellular processes, TIL are unable to elicit cytotoxic mechanisms regardless of CI treatment. Recent literature has suggested that the ectoenzyme CD38 plays a critical role in regulating not only the harsh metabolic milieu of the TME but of T cell effector function as well. Most notably CD38 regulates cellular energetics by metabolizing the cofactor NAD+, thus removing an essential electron carrier and substrate required for numerous cellular processes. Interestingly, CD38 metabolizes NAD+ via one of two separate reactions, cyclase or hydrolase, thus producing two products. Our central hypothesis is that small molecule inhibitors of CD38 will promote phenotypic reprogramming of T cells, allowing for heightened effector function. Our group has identified CD38 activity-selective small molecule inhibitors that can be used to explore the significance of these two CD38-dependent biochemical reactions on T cell effector function and metabolism. These inhibitors were identified via screening of a curated small molecule library against CD38. Further investigation of enzyme kinetics revealed both cyclase and hydrolase hit compounds inhibit CD38 through uncompetitive mechanisms. Focusing on reaction specificity, our hit compounds are being optimized to explore uncompetitive inhibition of the CD38:NAD complex. Optimized activity-selective inhibitors will allow more detailed mechanistic studies of the role of CD38 and NAD+ in immunometabolism, and could also result in the development of first-in-class immunotherapeutic agents.

Design, synthesis, and biological evaluation of CD38 inhibitors for the treatment of cancer

ACS Spring Meeting 2021

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