USP22 Inhibitors for Cancer Therapeutics and Anti-tumor Immunity

NU 2021-018

INVENTORS

Deyu Fang*

Elena Montauti

Ming Yan

Beixue Gao

SHORT DESCRIPTION

Small molecule inhibitors of ubiquitin specific protease 22 that demonstrate antitumor activity and enhancement of the immune system in preclinical models

BACKGROUND

Tumors can create a highly immunosuppressive tumor microenvironment (TME) that favors immune regulatory functions over anti-tumor responses. Particularly, the TME favors T regulatory (Treg) cell stability and function, while diminishing the antitumor activity of effector T cells. As shown in the figure, intratumoral Treg (itTreg) cells are altered by the TME to heighten their proliferative and suppressive abilities, including displaying upregulated expression of the Treg transcription factor, Forkhead Box P3 (FoxP3). FoxP3 functions to enhance Treg fitness by augmenting Treg cell stability and suppressive molecular function. Although FoxP3 is uniquely important for Treg identify and function, it is an intracellular protein whose targeting would require great care as complete inhibition would likely drive significant autoimmunity. Therefore, superior therapeutic candidates would be those that control the expression and stability of FoxP3 specifically in the TME. Ubiquitination acts as a critical process to modulate FoxP3 and Treg cells, and its modulation may serve as an effective target for cancer therapeutics.

ABSTRACT

Ubiquitin specific peptidases (USPs) serve as naturally occurring modulators for deubiquitination at the transcriptional and/or posttranslational level. Northwestern inventors have utilized computational modeling and virtual screening to identify an initial lead compound for USP22 that selectively inhibits Foxp3 expression levels in Treg cells, suppresses tumor growth, and enhances anti-tumor immunity in syngeneic mouse tumor models. Further computational modeling and screening based on the lead compound generated more compounds with potentially improved USP22 inhibitory activity. Early in vitro studies in Treg cells demonstrate comparable cytotoxicity and greater USP22 inhibitory activity than the initial compound. Later studies aim to test improved compounds in the previously used syngeneic mouse models. Their initial studies suggest that USP22 is important in maintaining FOXP3 expression and thus Treg fitness in the TME through multiple pathways. These compounds demonstrate specific and efficacious USP22 inhibition and can be used for both therapeutic applications for anti-tumor therapy and immunity enhancement as well as a research tool to study USP22-related function and activity.

APPLICATIONS

Antitumor therapy for multiple cancers including lung cancer, lymphoma, melanoma, and colon cancers
Immune response enhancer for infectious disease treatment and/or boosting vaccination
Pharmacological research tool to study USP22

ADVANTAGES