Arginase (ARG) is an enzyme that metabolizes arginine to ornithine and urea. The role of ARG1, secreted by myeloid derived suppressor cells (MDSCs) in the tumor microenvironment, has become increasingly recognized as an important mechanism of tumor immune evasion by (1) depriving T cells of arginine and  (2) increasing the concentration of immunosuppressive metabolites.<br/>Here we present the design, synthesis, and evaluation of a class of boronic acids featuring novel N-containing heterocycles as potent ARG1 inhibitors, which were discovered through modeling enabled structure based drug design (SBDD) from a known and moderately active inhibitor, ABH. Subsequent optimization efforts aimed at overcoming significant challenges associated with the unique physicochemical properties of this chemotype, especially sub-optimal oral bioavailability, will be highlighted. These efforts were greatly accelerated by the development of novel synthetic methods & strategies towards highly stereo-selective late-stage transformations, e.g. stereo-convergent reduction via H-bond template, direct C-H functionalization via photo-excitation and hydrogen atom transfer. As a result, a lead series was identified which demonstrated a favorable overall profile with superior potency and pharmacokinetics. Furthermore, the pharmacological evaluation of lead compounds will also be presented.

Design, synthesis, and evaluation of novel arginase1 (ARG1) inhibitors for cancer immunotherapy

ACS Spring Meeting 2021

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