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

Abstract

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.

Water Thermodynamics of Peptide Toxin Binding Sites on Ion Channels

“…Moreover, extensive retrospective work has established that these water site free energies correlate with experimentally measured binding free energies for both small molecules [ 18 , 27 , 28 ] and peptides [ 25 ], as was predicted from theory [ 23 ], although in practice prediction of free energies is now performed using free-energy perturbation [ 29 , 30 ]. Nonetheless, prospective studies from drug discovery programs have since demonstrated that displacement or replacement of a water molecule from an unstable site will reliably contribute favorably to binding, and thus these water sites can serve to guide the placement of functional groups for optimizing potency [ 31 , 32 ]. As a result, interpreting peptide toxin interactions with ion channels in terms of the water sites they displace or replace upon binding might present a new framework for understanding peptide toxin potency and SAR.…”

DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer

“…On the contrary, compound 41 is a reversible, highly potent, selective, and orally bioavailable USP7 inhibitor. In in vivo xenograft models of multiple myeloma, this molecule impairs the tumor growth of both p53 wild-type and mutant tumor cell lines, confirming that USP7 inhibition can suppress tumor growth affecting different pathways [171].…”

“…[195][196][197][198] IP: intraperitoneal; IV: intravenous; SC: subcutaneous. C19 [167] Spongiacidin C [169] XL177A [170] Compound 41 [171] [171]…”

In silico evaluation of drugs used in treatment of oral lichen planus

“…A number of SBDD studies have successfully used Schrodinger suite of applications for drug designing, drug repurposing, understanding drug interaction at receptor site, and property analysis 22,23 . Models for selective lipoxygenase inhibitors, design principles for non‐nucleoside inhibitors for HIV‐1 reverse transcriptase (NNRTIs), design, and validation of tumor growth inhibitors are few examples of the wide range of application of SBDD using Schrodinger suite of applications 24–27 …”

“…22,23 Models for selective lipoxygenase inhibitors, design principles for non-nucleoside inhibitors for HIV-1 reverse transcriptase (NNRTIs), design, and validation of tumor growth inhibitors are few examples of the wide range of application of SBDD using Schrodinger suite of applications. [24][25][26][27] The present study evaluates the action of the commonly used drugs for treating OLP at HSP70 and TNFα using molecular docking. Through this study, we attempt to understand the interaction of drug at target site and discuss the clinical utility and future possibility of such studies.…”