Discovery of A031 as effective proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader for the treatment of prostate cancer

Chen, Linrong; Han, Liuquan; Mao, Shujun; Xu, Ping; Xu, Xinxin; Zhao, Ruibo; Wu, Zhihua; Zhong, Kai; Yu, Guangliang; Wang, Xiaolei

doi:10.1016/j.ejmech.2021.113307

Cited by 37 publications

(20 citation statements)

References 51 publications

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“…reported success in the development of VHL-based AR PROTACs by optimising AR antagonists and E3 ligase ligands that potently induced the degradation of AR. 42 As a potent AR degrader, PROTAC 14 ( Table 3 ) could induce the degradation of AR protein in VCaP cell lines in a time-dependent manner, achieving the IC 50 value of less than 0.25 μM. PROTAC 14 was five times less toxic than EZLA and worked with an appropriate half-life (t 1/2 ) or clearance rate.…”

Section: Protacs For Cancersmentioning

confidence: 99%

“…designed and synthesised a new series of CRBN-based PROTACs using newly discovered AR antagonists. 42 The cell inhibitions for all of these synthetic compounds in AR + VCaP cell lines at different concentrations were tested. The representative compound, PROTAC 3 ( Table 2 ), effectively inhibited 50.44% of cell liability at 1.0 μM.…”

Section: Protacs For Cancersmentioning

confidence: 99%

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Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

Wang

Zhang

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic institutions, large pharmaceutical enterprises, and biotechnology companies. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The heterobifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. To date, PROTACs targeting ∼70 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for diseases therapy. In this review, the recent advances in PROTACs against clinically validated drug targets are summarised and the chemical structure, cellular and in vivo activity, pharmacokinetics, and pharmacodynamics of these PROTACs are highlighted. In addition, the potential advantages, challenges, and prospects of PROTACs technology in disease treatment are discussed.

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Section: Protacs For Cancersmentioning

confidence: 99%

Section: Protacs For Cancersmentioning

confidence: 99%

Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

Wang

Zhang

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In order to find PROTACs with lower toxicity and better binding affinity than before, Wang group designed and synthesized several series of AR PROTACs by using CRBN/VHL E3 ligands and AR antagonists in 2021. 24 They tested the cell inhibition of these synthetic compounds in AR-positive VCaP cells at different concentrations, and the degrader 8 ( A031 , Fig. 4 ) could inhibit 69.56% of the cell viability under 1.0 µM.…”

Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 99%

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Cao

et al. 2022

Sig Transduct Target Ther

136

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PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

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“…Other AR-targeted PROTAC molecules with animal testing data include TD-802 (DC 50 = 12.5 nM) ( 32 ) and A031 (IC 50 < 0.25 μM) ( 33 ) that promote degradation of the full-length AR protein. MTX-23 was shown to promote protein degradation of both the full-length and AR-V7 variant AR protein (DC 50 = 0.37-2 μM) ( 34 ).…”

Section: Ar Protein Elimination Approaches In Preclinical Development...mentioning

confidence: 99%

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

Huang

Lin

2022

Front. Oncol.

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Prostate cancer is a major health issue in western countries and is the second leading cause of cancer death in American men. Prostate cancer depends on the androgen receptor (AR), a transcriptional factor critical for prostate cancer growth and progression. Castration by surgery or medical treatment reduces androgen levels, resulting in prostatic atrophy and prostate cancer regression. Thus, metastatic prostate cancers are initially managed with androgen deprivation therapy. Unfortunately, prostate cancers rapidly relapse after castration therapy and progress to a disease stage called castration-resistant prostate cancer (CRPC). Currently, clinical treatment for CRPCs is focused on suppressing AR activity with antagonists like Enzalutamide or by reducing androgen production with Abiraterone. In clinical practice, these treatments fail to yield a curative benefit in CRPC patients in part due to AR gene mutations or splicing variations, resulting in AR reactivation. It is conceivable that eliminating the AR protein in prostate cancer cells is a promising solution to provide a potential curative outcome. Multiple strategies have emerged, and several potent agents that reduce AR protein levels were reported to eliminate xenograft tumor growth in preclinical models via distinct mechanisms, including proteasome-mediated degradation, heat-shock protein inhibition, AR splicing suppression, blockage of AR nuclear localization, AR N-terminal suppression. A few small chemical compounds are undergoing clinical trials combined with existing AR antagonists. AR protein elimination by enhanced protein or mRNA degradation is a realistic solution for avoiding AR reactivation during androgen deprivation therapy in prostate cancers.

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Discovery of A031 as effective proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader for the treatment of prostate cancer

Cited by 37 publications

References 51 publications

Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

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