title: Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47.
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.
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Weinstock
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Cao
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Kingsbury
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: McDermott
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Kodrasov
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: Devin M
authors.initials: DM
authors.lastname: McKelvey
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: K G
authors.initials: KG
authors.lastname: Suresh Kumar
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Goldenberg
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Mattern
authors.affiliation: Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nicholson
keywords: Polβ; Ubiquitin isopeptidase; deubiquitylase; p53