# Novel small molecule USP7 Inhibitors for p53 activation and cancer therapy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $370,575

## Abstract

Project Summary:
 The long-term objective of this project is to develop a novel targeted therapy for human cancers by
reactivating the tumor suppression pathways. Although p53 is frequently mutated in almost 50% of human
cancers, many human tumors retain wild-type p53 but its activities are downregulated through multiple
mechanisms. Inactivation of Mdm2 is a validated approach for the treatment of human cancer retaining wild-type
p53 by reactivating the p53 tumor suppressor function. Through nearly two decades of intense efforts, a number
of highly potent small-molecule inhibitors and peptides that inhibit the MDM2–p53 interaction (also called Mdm2
inhibitors) have been successfully developed and validated in vitro, and several of these Mdm2 inhibitors have
been moved to human clinical trials for in vivo validation. Nevertheless, some serious challenges remain to be
addressed. The major issue is the dose-limiting toxicity because of low efficacy and severe toxicity to normal
tissues with increasing dosage of these Mdm2 inhibitors. Moreover, emergence of p53 mutations in cancer
patients developed highly resistance after the initial treatment with Mdm2 inhibitors. Thus, additional cancer
targets aiming at this pathway are clearly needed for more effective therapeutic purpose. In this application, we
plan to characterize novel small molecule USP7 inhibitors in activating p53 and cancer therapy. The
deubiquitinase USP7 (also called HAUSP) was one of the first deubiquitinases (DUBs) that exhibit a specific role
in regulating protein stability in vivo. Previous studies from our lab and others demonstrated that inhibition of
USP7 leads to p53 activation by destabilizing both Mdm2 and Mdmx. Notably, USP7 inhibitors are also able to
induce p53-independent tumor suppression functions in vivo. For example, we identified N-Myc, a major driver
in neuroblastoma tumorigenesis as a critical target for USP7. Recently, we discovered PD-L1 as another
important target of USP7. Taken together, these studies reveal that USP7 inhibitors have better efficacy because
USP7 inhibition activates p53-mediated tumor suppression by downregulating both Mdm2 and Mdmx and also
induces p53-independent tumor growth suppression by destabilizing N-Myc and PD-L1. Moreover, the tumors
with high levels of N-Myc or PD-L1 may not develop drug resistance even when the p53 gene is mutated. The
major hypothesis to be tested here is whether USP7 inhibitors are more effective and better therapeutic agents
for the treatment of human cancers. In Aim 1, we will further characterize novel USP7 inhibitors obtained from
our high-through-put screening assays in suppressing tumor growth through both p53 activation and N-Myc
destabilization in human neuroblastomas. In Aim 2, we will examine whether the USP7 inhibitor is able to
promote immunotherapy by downregulating PD-L1 in human cancer cells.

## Key facts

- **NIH application ID:** 10093308
- **Project number:** 1R01CA254970-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Wei Gu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,575
- **Award type:** 1
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093308

## Citation

> US National Institutes of Health, RePORTER application 10093308, Novel small molecule USP7 Inhibitors for p53 activation and cancer therapy (1R01CA254970-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10093308. Licensed CC0.

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