New approaches are urgently needed against difficult-to-target cancer-related proteins that are “undruggable” by conventional classes of drugs. The National Institute of General Medical Sciences has awarded a five-year, $2.3 million grant to Juan Pablo Maianti, Ph.D., to develop a precision-targeted oxidation strategy to inhibit currently undruggable protein interfaces. Dr. Maianti discovered this new mode of inhibition by using small drug-like molecules that selectively transfer a single oxygen atom onto a targeted protein’s amino-acid sidechain. While most small-molecule drugs bind such challenging targets only temporarily, Dr. Maianti’s strategy produces a chemically stable and site-specific oxidation that potently and durably blocks the protein interface.

Dr. Maianti and his team will first apply their strategy to improve the effectiveness and scope of immune-checkpoint inhibitors. These inhibitors bolster the immune system to attack cancers but don’t always work against solid tumors, brain tumors, and other cancers shielded from immune attack. This new mode of irreversible inhibition could yield improved treatment options for immuno-oncology and for other diseases with no available treatment options.

Dr. Maianti is an assistant professor of biochemistry at Einstein, a member of the National Cancer Institute–designated Montefiore Einstein Comprehensive Cancer Center, and scientific director of the Chemical Synthesis Core. (1R35GM160115-01)