Covalent PRC2 Inhibitors for Advanced Cancer Therapeutics

SHORT DESCRIPTION

Covalent inhibitors and proteolysis-targeting chimera (PROTAC) degraders targeting components of the PRC2 complex (EZH and EED) to block both enzymatic and non-enzymatic functions, offering robust anti-tumor efficacy.

INVENTORS

• Gary Schiltz (Weinberg College of Arts and Sciences, Department of Chemistry)*
• Jindan Yu (Feinberg School of Medicine, Department of Medicine (Hematology & Oncology Division))* - **Now at Emory**

* Principal Investigator

DEVELOPMENT STAGE

TRL-4 Prototype Validated in Lab: Key functions have been demonstrated in the lab including target binding, specificity, inhibition, and degradation as well as proof-of-concept for robust anti-tumor activity via in vitro and in vivo efficacy studies.

NU Tech ID 

NU 2020-217 (NU 2020-215, NU 2020-216, NU 2020-217)

IP STATUS

Multiple Issued US Patents

(US12042543B2, US12491252B2, US11919855B2, US11981678B2, US12492209B2).

BACKGROUND

Cancer remains a leading cause of death with nearly 1.9 million new diagnoses annually in the United States (American Cancer Society). Existing treatments for cancers such as prostate, lymphoma, and breast often show limited efficacy and come with significant side effects. Conventional small molecule inhibitors struggle with drug resistance and transient target engagement leading to modest efficacy. This unmet medical need drives the search for next-generation therapies that overcome these limitations. Epigenetic regulators like PRC2 play key roles in gene silencing and are frequently dysregulated in cancer, driving uncontrolled cell proliferation. Current cancer treatments targeting components of the PRC2 complex such as EZH2 often rely on reversible enzyme inhibitors that leave non-enzymatic oncogenic functions unchecked. There is an urgent need for improved therapies that address both catalytic and non-catalytic activities of EZH2 and other components of the PRC2 complex.

ABSTRACT

Northwestern researchers have developed novel inhibitors of the PRC2 complex by synthesizing a series of small molecules that covalently inhibit and promote targeted degradation of EZH2 and EED using PROTAC technology. This approach disrupts the epigenetic regulation driven by PRC2 and blocks both the enzymatic and non-enzymatic functions of the PRC2 complex, thereby inhibiting cancer cell proliferation. Laboratory studies demonstrate robust and long-lived target engagement that drives significant anti-tumor effects in vivo. This dual mechanism provides a comprehensive strategy to overcome limitations of current reversible inhibitors and represents a novel next-generation anticancer therapeutic.

APPLICATIONS

• Treatment for multiple types of cancer including prostate cancer, lymphoma, melanoma, and breast cancer.

ADVANTAGES

• Superior efficacy at lower doses: Blocks both catalytic and non-catalytic functions for robust anti-tumor activity.
• Long-lived target engagement: Demonstrates sustained inhibition and improved therapeutic outcomes in vivo.
• Enhanced safety profile: Potentially reduces side effects compared to conventional inhibitors.
• Targeting multiple components of the PRC2 complex (EZH2 and EED) for enhanced efficacy.

PUBLICATIONS

• Gary Schiltz, Jindan Yu, et al. Small Molecule Approaches for Targeting the Polycomb Repressive Complex 2 (PRC2) in Cancer J Med Chem, Dec 7, 2020
• Gary Schiltz, Jindan Yu, et al. EZH2 PROTACs outperform catalytic inhibitors in prostate cancer by targeting a methylation-independent function of PRC2 Oncogene, Jan 7, 2026