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Intracellular proteins play a central role in maintaining the healthy functions of cells. Aberrant proteins or dysregulated protein levels in the cell can cause a variety of diseases, such as cancer, diabetes, auto-immune diseases, inflammatory and neurodegenerative disorders. One of the major pathways for maintaining physiological levels of regular proteins and breaking down unwanted substrates is the highly regulated ubiquitin-proteasome system (UPS), which was discovered by Aaron Ciechanover, Avram Hershko and Irwin Rose for which they were jointly awarded the 2004 Nobel Prize in Chemistry.

In the UPS, through an enzymatic cascade, substrate proteins to be downregulated are marked by a chain of ubiquitins, an essential and highly conserved 76 amino acid polypeptide co-factor, as a signal for subsequent proteasomal degradation. The UPS participates in a wide array of biological functions such as signal transduction, immune response, apoptosis, DNA damage repair, regulation of gene transcription and cell cycle control, and activation of NF-κB.

The Nobel Prize in Chemistry 2004. NobelPrize.org. Nobel Media AB 2020. Thu. 9 Apr 2020.

  • Irwin Rose

  • Aaron Ciechanover

  • Avram Hershko

The ubiquitination-proteasome pathway involves several main steps: ubiquitination, recognition, degradation and deubiquitination. Specifically, ubiquitin is first activated by forming a link to E1 activation enzyme, and is then transferred onto an E2 conjugating enzyme. Subsequently, enzyme E3 ligase catalyzes the rapid transfer of the ubiquitin from E2 to a Lys-amino group of substrate proteins or a ubiquitin unit already attached to the substrate proteins. Upon being linked to a chain of ubiquitin molecules, the substrate proteins will ultimately be degraded by the 26S proteasome with the ubiquitin moieties being recycled by the deubiquitinating enzymes (DUBs) for re-use.

Figure 1. The schematic representation of the UPS pathway

The ubiquitin‐proteasome pathway is essential to nearly all aspects of cell biology. As a result, modulating the intracellular pathway to destruct pathogenic proteins offers enormous opportunities in the area of drug discovery and development. One of the particular components of the pathway targeted for drug development is E3 ubiquitin ligase.

Figure 2. The UPS pathway is associated with many types of human diseases

Recently, cereblon (CRBN), a 442-amino acid protein, has been identified as a substrate receptor of the CRBN-CRL4 E3 ligase complex (CRL4CRBN) targeted by a class of immunomodulatory small molecule drugs, including thalidomide and its derivatives lenalidomide and pomalidomide.

A growing body of evidence has shown that substrate binding specificity of the CRL4CRBN E3 ligase complex can be modulated by thalidomide and its analogs, leading to recruitment and accommodation of new, non-intrinsic substrates for ubiquitination and degradation. Four neo-substrates of the CRL4CRBN E3 ligase complex have been well characterized: Ikaros (IKZF1) and Aiolos (IKZF3), two important members of the Ikaros family of zinc-finger transcription factors responsible for the maturation of B cells, CK1α and GSPT1.

Modulating substrate specificity of CRL4CRBN E3 ligase complex via novel small molecules to destroy disease-associated proteins, particularly those that lack discrete catalytic domains amenable to small-molecule inhibition, has tremendous potential and a bright future in the drug development field.

Over the past several years, Kangpu Biopharmaceuticals has established a broad and solid pipeline covering novel generation of small molecular entities that modulate CRL4CRBN E3 ligase complex with promising potential for the treatment of solid tumors, hematological malignancies, auto-immune diseases as well as inflammatory disorders.