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      Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery

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          An overview of the latest developments in PROTAC technology and the possible directions of this approach is presented.


          Curing malignant carcinomas is a grand ambition in the development of human health. Over the past decades, targeted therapies have become one of the most successful ways of achieving this. Of these approaches, small molecule inhibitors and monoclonal antibodies are two major methods, however several barriers to their development and clinical use still exist. The use of proteolysis-targeting chimeras (PROTACs) is a new technology through utilizing a intracellular ubiquitin-proteasome system to induce targeted protein degradation, is receiving much attention in the field of targeted therapies. Hetero-bifunctional PROTACs have the potential to eliminate the “undruggable” proteome that comprises about 85% of human proteins, which indicates their great prospects in therapeutic fields. However, there are some hurdles preventing current PROTACs moving from bench to clinic, such as delivery and bioavailability. This review provides an overview of the development of PROTAC technology and will briefly summarize the future possible directions of this approach.

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          Most cited references 81

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          Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.
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            The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy.
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              Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.

              Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.

                Author and article information

                RSC Advances
                RSC Adv.
                Royal Society of Chemistry (RSC)
                May 30 2019
                : 9
                : 30
                : 16967-16976
                [1 ]Shanghai Key Laboratory of Regulatory Biology
                [2 ]The Institute of Biomedical Sciences
                [3 ]School of Life Sciences
                [4 ]East China Normal University
                [5 ]Shanghai 200241
                [6 ]School of Chemistry and Molecular Engineering
                [7 ]China
                © 2019


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