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Drug discovery in the ubiquitin regulatory pathway
Brian R Wong1, Francesco Parlati, Kunbin Qu
1Rigel Pharmaceuticals, 1180 Veterans Blvd South San Francisco, CA 94080, USA. bwong@rigel.com
Abstract:
The ubiquitin system has been implicated in the pathogenesis of numerous disease states, including oncogenesis, inflammation, viral infection, CNS disorders and metabolic dysfunction. Ubiquitin conjugation and deconjugation to substrate proteins is carried out by multiple families of proteins, each with a defined role in the enzymatic cascade. This conjugation-deconjugation system parallels the kinase-phosphatase system in that both alter protein function by the addition and removal of post-translational modifiers. Our understanding of ubiquitin biology and strategies to interfere pharmacologically with the ubiquitin regulatory machinery is progressing rapidly. In light of increased interest in ubiquitin pathways as drug targets, we review the ubiquitin enzymatic cascades, highlighting therapeutic opportunities and enzymatic mechanisms. We also discuss the challenges of targeting this class of enzymes with small molecules, as well as current approaches and progress in drug discovery.
Insights
The ubiquitin system regulates protein function and is crucial in diseases like cancer and inflammation. Targeting these ubiquitin enzymes offers new therapeutic strategies for drug discovery.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- The ubiquitin system is integral to numerous disease states, including oncogenesis, inflammation, viral infection, CNS disorders, and metabolic dysfunction.
- Ubiquitin conjugation and deconjugation involve multiple protein families, forming enzymatic cascades analogous to kinase-phosphatase systems.
- Post-translational modification by ubiquitin addition/removal alters substrate protein function.
Purpose of the Study:
- To review the ubiquitin enzymatic cascades.
- To highlight therapeutic opportunities and enzymatic mechanisms within the ubiquitin system.
- To discuss challenges and progress in developing small molecule drugs targeting ubiquitin-modifying enzymes.
Main Methods:
- Literature review of ubiquitin biology and drug discovery efforts.
- Analysis of enzymatic mechanisms in ubiquitin conjugation and deconjugation.
- Examination of therapeutic strategies targeting ubiquitin pathways.
Main Results:
- Ubiquitin pathways are increasingly recognized as critical drug targets.
- Significant progress has been made in understanding ubiquitin biology and pharmacological intervention strategies.
- Various therapeutic opportunities exist within the ubiquitin enzymatic cascades.
Conclusions:
- The ubiquitin system presents a rich area for therapeutic intervention across multiple disease types.
- Targeting ubiquitin-modifying enzymes with small molecules is a rapidly advancing field in drug discovery.
- Overcoming challenges in small molecule drug development is key to realizing the full therapeutic potential of targeting the ubiquitin system.