Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47
Joseph Weinstock1, Jian Wu1, Ping Cao1
1Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
Abstract:
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 1, 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 1 has been shown to demonstrate modest 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, analogues of compound 1 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.
Insights
New dual inhibitors targeting human ubiquitin-specific proteases 7 (USP7) and 47 (USP47) show potential for cancer therapy by stabilizing p53 and inducing apoptosis. Analogs improved potency and developability for treating multiple myeloma and prostate cancer.
Area of Science:
- Oncology
- Biochemistry
- Medicinal Chemistry
Background:
- Human ubiquitin-specific proteases 7 (USP7) and 47 (USP47) are cancer-related enzymes.
- Inhibiting USP7 and USP47 may offer therapeutic benefits by stabilizing tumor suppressor p53 and reducing DNA polymerase β (Polβ).
Purpose of the Study:
- To discover and develop novel dual small molecule inhibitors of USP7 and USP47 for cancer treatment.
- To improve the potency, solubility, and metabolic profile of initial lead compounds.
Main Methods:
- Discovery of a new class of dual small molecule inhibitors targeting USP7 and USP47.
- Synthesis and testing of analogues of Compound 1 to enhance drug-like properties.
- In vitro evaluation of cellular inhibition, p53 stabilization, and apoptosis induction.
- In vivo assessment of anti-cancer activity in multiple myeloma and B-cell leukemia xenograft models.
Main Results:
- Compound 1 selectively inhibits USP7 and USP47, demonstrating cellular USP7 inhibition, p53 elevation, and apoptosis in cancer cell lines.
- Compound 1 exhibited modest anti-cancer activity in human xenograft models of multiple myeloma and B-cell leukemia.
- Analogue synthesis led to significant improvements in inhibitor potency, solubility, and metabolic stability.
Conclusions:
- Dual inhibition of USP7 and USP47 represents a promising strategy for cancer therapy.
- Optimized analogues of Compound 1 show potential as preclinical and clinical candidates for multiple myeloma, prostate cancer, and other malignancies.
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