Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer

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

doi:10.1021/acs.jmedchem.1c00882

Cited by 90 publications

(115 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, several orally bioavailable compounds have been developed that fall outside the rule of 5 parameters. These compounds typically have higher molecular weights and a higher number of hydrogen-bond acceptors than the rule dictates, but particular attention must also be paid to hydrogen-bond donors, topological polar surface area and cLogP 61 , as well as lipophilic efficiency 62 – 64 and other physicochemical parameters 65 , including those summarized in a recent review 66 . Short linkers can be used to modulate PROTAC molecular weights 67 and properties 65 , but ‘linker-ology’ does more than link the POI and E3 warheads together and influence properties.…”

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

“…These compounds typically have higher molecular weights and a higher number of hydrogen-bond acceptors than the rule dictates, but particular attention must also be paid to hydrogen-bond donors, topological polar surface area and cLogP 61 , as well as lipophilic efficiency 62 – 64 and other physicochemical parameters 65 , including those summarized in a recent review 66 . Short linkers can be used to modulate PROTAC molecular weights 67 and properties 65 , but ‘linker-ology’ does more than link the POI and E3 warheads together and influence properties. The linker can contribute to the PROTAC solution conformation 68 and degradation efficiency (DC 50 /D max ) 69 , and influence the E3 ligase–POI interactions and presentation of the POI within the zone of ubiquitylation (Fig.…”

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

See 1 more Smart Citation

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,290

996

View full text Add to dashboard Cite

Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology.

show abstract

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,290

996

View full text Add to dashboard Cite

show abstract

“…In 2021, they used CRBN ligand to replace the VHL ligand and obtained the degrader 4 ( ARD-2128 , Fig. 4 ), 19 which achieved 67% oral bioavailability in mice. Oral administration of 4 ( ARD-2128 ) could effectively induce degradation of AR protein and effectively inhibit the growth of tumors 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

114

103

View full text Add to dashboard Cite

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.

show abstract

“…Since the publication of the initial discovery of ARD-61, the authors continued their research and have published an additional study where the PROTAC was tested specifically against enzalutamide-resistant (Enz R ) cell lines with great success compared to the inhibitor alone, resulting in an IC 50 of 472 nM against the aggressive CWR-R1 Enz R cell line and similar effects in other CRPC lines ( Kregal et al, 2020 ). After the success of their previous compounds, the Wang lab developed a CRBN-recruiting AR-PROTAC ARD-2128 ( Figure 3 ) with good oral bioavailability (67% in mice) ( Han et al, 2021 ). However, the AR antagonists-derived PROTACs will not be effective in CRPC with AR-SVs such as AR-V7 that lack the LBD.…”

Section: Protacs Targeted Towards Treatment Of Various Types Of Drug ...mentioning

confidence: 99%

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Burke

Smith

Zheng

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Cancer drug resistance presents a major barrier to continued successful treatment of malignancies. Current therapies inhibiting proteins indicated in cancer progression are consistently found to lose efficacy as a result of acquired drug resistance, often caused by mutated or overexpressed protein targets. By hijacking the cellular ubiquitin-proteasome protein degradation machinery, proteolysis-targeting chimeras (PROTACs) offer an alternative therapeutic modality to cancer treatments with various potential advantages. PROTACs specific for a number of known cancer targets have been developed in the last 5 years, which present new options for remission in patients with previously untreatable malignancies and provide a foundation for future-generation compounds. One notable advantage of PROTACs, supported by evidence from a number of recent studies, is that they can overcome some of the resistance mechanisms to traditional targeted therapies. More recently, some groups have begun researching the use of PROTACs to successfully degrade mutated targets conferring cancer resistance against first-line treatments. In this review, we focus on analyzing the developments in PROTACs geared towards cancer resistance and targets that confer it in the search for new and successful therapies.

show abstract

Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer

Cited by 90 publications

References 61 publications

PROTAC targeted protein degraders: the past is prologue

PROTAC targeted protein degraders: the past is prologue

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

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Contact Info

Product

Resources

About