Inhibitors of the cancer-related cysteine isopeptidase human ubiquitin-specific proteases 7 (USP7) and 47 (USP47) are considered to have potential as cancer therapeutics owing to their ability to stabilize the tumor suppressor p53 and to decrease DNA polymerase b. A new class of dual small molecule inhibitors of these enzymes has been discovered. P005091,  a selective inhibitor of USP7 and USP47 with moderate potency, demonstrates inhibition of USP7 in cells and induces elevated p53 and apoptosis in cancer cell lines. P005091 demonstrates activity in human xenograft multiple myeloma and B-cell leukemia in vivo models. This activity may be the result of dual inhibition of USP7 and USP47. To address issues regarding potency and developability, P005091 analogs have been synthesized and tested, leading to improvements in potency, solubility, and metabolic reactivity profile. Further optimization is expected to yield preclinical candidates and, ultimately, clinical candidates for the treatment of certain cancers.

Selective dual inhibitors of the cancer-related deubiquitylating proteases USP7 and USP47

244th National Meeting (2012)

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