Discovery of ARD-2585 as an Exceptionally Potent and Orally Active PROTAC Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer

Xiang, Weidong; Zhao, Lijie; Han, Xin; Qin, Chong; Miao, Bo; McEachern, Donna; Wang, Yu; Metwally, Hoda; Kirchhoff, Paul D.; Wang, Lu; Matvekas, Aleksas; He, Miao; Wen, Bo; Sun, Duxin; Wang, Shaomeng

doi:10.1021/acs.jmedchem.1c00900

Cited by 91 publications

(113 citation statements)

References 27 publications

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“…4 ). 20 They found that the new degrader 5 ( ARD-2585 ) had a significant increase in the degradation activity of AR in LNCaP cells and VCaP cells with the DC 50 of 0.1 nM and 0.04 nM, respectively, also it could effectively inhibit cell growth in those cell lines with the IC 50 values of 1.5 nM and 16.2 nM, respectively. Moreover, it achieved excellent pharmacokinetics and 51% oral bioavailability in mice.…”

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

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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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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

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“…described some AR PROTACs using the CRBN ligand, thalidomide, and different classes of AR antagonists. 45 PROTAC 6 ( Table 2 ) achieved picomolar DC 50 values and >98% of D max in the VCaP cell line with a wild-type AR and in the LNCaP cell line carrying a T878A-mutated AR mutant. Moreover, PROTAC 6 reduced AR protein by >80% at 0.1 nM in the 22Rv1 cell line carrying an AR-V7 variant and at 1 nM in the MDA-PCa-2b cell line carrying a double AR mutation.…”

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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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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“…The AR degrader (ARD) series of PROTAC molecules (ARD-61, -69, -266, -2128, -2585) were reported from Dr. Wang's group at the University of Michigan (27)(28)(29)(30)(31). Their latest molecule, ARD-2585, is a potent (DC 50 < 0.1 nM) oral agent and has at least 10-fold more potent than ARV-110 (27).…”

Section: Protac Technologymentioning

confidence: 99%

Section: Protac Technologymentioning

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 ARD-2585 as an Exceptionally Potent and Orally Active PROTAC Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer

Cited by 91 publications

References 27 publications

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

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

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

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

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