Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity

USP7
is a promising target for cancer therapy as its inhibition
is expected to decrease function of oncogenes, increase tumor suppressor
function, and enhance immune function. Using a structure-based drug
design strategy, a new class of reversible USP7 inhibitors has been
identified that is highly potent in biochemical and cellular assays
and extremely selective for USP7 over other deubiquitinases. The succinimide
was identified as a key potency-driving motif, forming two strong
hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial
benzofuran-amide scaffold
yielded a simplified ether series of inhibitors, utilizing acyclic
conformational control to achieve proper amine placement. Further
improvements were realized upon replacing the ether-linked amines
with carbon-linked morpholines, a modification motivated by free energy
perturbation (FEP+) calculations. This led to the discovery of compound 41, a highly potent, selective, and orally bioavailable USP7
inhibitor. In xenograft studies, compound 41 demonstrated
tumor growth inhibition in both p53 wildtype and p53 mutant cancer
cell lines, demonstrating that USP7 inhibitors can suppress tumor
growth through multiple different pathways.