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Publications Highlighting Screening Mechanisms for Ubiquitin Ligase Inhibitors

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Rigel Pharmaceuticals, Inc. has announced two publications in the October 24 issue of Methods in Enzymology (Volume 399) relating to its ubiquitin ligase program.

Ubiquitin ligases are enzymes that regulate protein degradation within the cell, affecting many important cellular functions, including cell division.

Targeting ligases represents an approach to treating diseases where normal cellular processes are out of balance.

“Ubiquitin ligases are important targets for the discovery of potential treatments for oncology, inflammatory and viral diseases,” said Donald G. Payan, M.D., executive vice president and chief scientific officer of Rigel.

“Since they are numerous and modular, these ligases provide the opportunity to intervene with a disease in a highly specific fashion, potentially improving efficacy and minimizing side-effects.”

The first publication highlights a Fluorescence Resonance Energy Transfer (FRET)-based assay that can monitor the kinetics of enzymatic activity across a wide range of ligases to give more detail about how the compounds work.

The second article details a high throughput screening process that Rigel has developed to screen the anaphase-promoting complex (APC), an E3 ubiquitin ligase under scrutiny as an anti-cancer target.

APC leads to degradation of key cell cycle proteins and is responsible for completing the final steps of mitosis. Therefore, APC inhibition may modulate cell proliferation and could have anti-tumor effects.

Rigel has been issued patents covering both of these ligase screening methodologies, and expects to receive additional patents in the area of ligase technology within the next year.

Ubiquitin modification of target proteins has been implicated in a wide array of cellular processes including cell biogenesis.

In order to better understand how Ubiquitin contributes to protein degradation and modification, Rigel scientists developed a homogenous, FRET-based assay that can monitor every reaction step involved in ubiquitin attachment to, or detachment from, substrate protein molecules.

The homogenous nature of the FRET assay was found to offer significant advantages over conventional methods.

This assay allowed researchers to monitor both ubiquitin polymerization and depolymerization reactions in the same reaction mixture.

In general, the homogenous FRET assay was found to have the potential to improve the throughput and reliability of screening for new drug leads in cancer biology.

In the study, researchers at Rigel established a plate-based in vitro ubiquitination assay that screens for small molecule inhibitors of APC E3 ligase activity.

The screen identified small molecule compounds that potently inhibit APC ligase activity.