Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges

Zeng, Shenxin; Huang, Wenhai; Zheng, Xiaoliang; Cheng, Liyan; Zhang, Zhimin; Wang, Jian; Shen, Zhengrong

doi:10.1016/j.ejmech.2020.112981

Cited by 136 publications

(106 citation statements)

References 188 publications

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“…For example, the development of drugs that induce the degradation of specific proteins has been making significant progress in recent years. PROTAC technology (proteolysis-targeting chimeras) exploits chemical entities to direct the ubiquitylation-mediated degradation of specific proteins 220 . Although still in preclinical development, there are multiple examples of the application of this technology to reduce the expression in cancer cells of protein kinases such as AKT, SGK3 and ABL [221][222][223] , which illustrates the potential of this approach if the challenge of translating it into clinical drugs can be overcome.…”

Section: The Next 20 Years Of Kinase Drug Discoverymentioning

confidence: 99%

Kinase drug discovery 20 years after imatinib: progress and future directions

Cohen

Cross

Jänne

2021

Nat Rev Drug Discov

625

465

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Section: The Next 20 Years Of Kinase Drug Discoverymentioning

confidence: 99%

Kinase drug discovery 20 years after imatinib: progress and future directions

Cohen

Cross

Jänne

2021

Nat Rev Drug Discov

625

465

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“…Compounds that degrade the AR, e.g., niclosamide and galeterone, or prevent AR-mediated transcription, e.g., bromodomain-containing protein 4 (BRD4) inhibitors, are promising therapeutic options in patients progressing after abiraterone and/or enzalutamide [ 68 , 69 , 70 ] ( Figure 2 ). Proteolysis targeting chimeras (PROTACs), also known as protein degraders, are a new class of small molecule therapeutics [ 71 ]. They differ from traditional inhibitors or antagonists in that they use a dual-binding system within each cancer cell to remove unwanted or damaged proteins.…”

Section: Ar-v7 Structure and Functionmentioning

confidence: 99%

AR-V7 in Metastatic Prostate Cancer: A Strategy beyond Redemption

Sobhani

Neeli

D’Angelo

et al. 2021

IJMS

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Metastatic prostate cancer is the most common cancer in males and the fifth cause of cancer mortality worldwide. Despite the major progress in this field, leading to the approval of novel anti-androgens, the prognosis is still poor. A significant number of patients acquire an androgen receptor splice variant 7 (AR-V7), which is constitutively activated and lacks the ligand-binding domain (LBD) while maintaining the nuclear localization signal and DNA-binding domain (DBD). This conformational change, even in the absence of the ligand, allows its retention within the nucleus, where it acts as a transcription factor repressing crucial tumor suppressor genes. AR-V7 is an important oncogenic driver and plays a role as an early diagnostic and prognostic marker, as well as a therapeutic target for antagonists such as niclosamide and TAS3681. Anti-AR-V7 drugs have shown promise in recent clinical investigations on this subset of patients. This mini-review focuses on the relevance of AR-V7 in the clinical manifestations of castration-resistant prostate cancer (CRPC) and summarizes redemptive therapeutic strategies.

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“…This fluorescence intensity loss was significantly reduced at a higher concentration of treatment, probably due to the hook effect of PROTAC molecules. 29 In sum, we successfully designed two NAMPT-oriented PROTAC compounds, SIAIS630120 (hereinafter referred to as 630120 ) and SIAIS630121 (hereinafter referred to as 630121 ), with effective degradation of the target protein.…”

Section: Resultsmentioning

confidence: 99%

Addressing Enzymatic-Independent Tumor-Promoting Function of NAMPT via PROTAC-Mediated Degradation

Fan

Yang

Jiang

et al. 2021

Preprint

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The rate-limiting enzyme of salvage pathway for NAD+ synthesis, NAMPT, is aberrantly overexpressed in a variety of tumor cells and is a poor prognosis factor for patient survival. NAMPT plays a major role in tumor cell proliferation, acting concurrently as an NAD+ synthase and unexpectedly, an extracellular ligand for several tumor-promoting signaling pathways. While previous efforts to modulate NAMPT activity were limited to enzymatic inhibitors with low success in clinical studies, protein degradation offers a possibility to simultaneously disrupt NAMPT enzyme activity and ligand capabilities. Here, we report the development of two highly selective NAMPT-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent NAMPT degradation in a cereblon-dependent manner in multiple tumor cell lines. Notably, both PROTAC degraders outperform a clinical candidate, FK866, in killing effect on hematological tumor cells. These results emphasize the importance and feasibility of applying PROTACs as a better strategy for targeting proteins like NAMPT with dual tumor-promoting functions, which are not easily achieved by conventional enzymatic inhibitors.

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Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges

Cited by 136 publications

References 188 publications

Kinase drug discovery 20 years after imatinib: progress and future directions

Kinase drug discovery 20 years after imatinib: progress and future directions

AR-V7 in Metastatic Prostate Cancer: A Strategy beyond Redemption

Addressing Enzymatic-Independent Tumor-Promoting Function of NAMPT via PROTAC-Mediated Degradation

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