1 research outputs found
Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47
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 β (Polβ),
both of which are potential anticancer effects. A new class of dual
small molecule inhibitors of these enzymes has been discovered. Compound <b>1</b>, 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. Compound <b>1</b> has been
shown to demonstrate modest activity in human xenograft multiple myeloma
and B-cell leukemia <i>in vivo</i> models. This activity
may be the result of dual inhibition of USP7 and USP47. To address
issues regarding potency and developability, analogues of compound <b>1</b> 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 multiple myeloma, prostate
cancer, and other cancers