Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance.
Jemilat Salami,Shanique B. Alabi,Ryan R. Willard,Nick J. Vitale,Jing Wang,Hanqing Dong,Meizhong Jin,Donald P. McDonnell,Andrew P. Crew,Taavi K. Neklesa,Craig M. Crews +10 more
- Vol. 1, Iss: 1, pp 100-100
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TLDR
A head-to-head comparison between a currently approved androgen receptor antagonist enzalutamide and its PROTAC derivative, ARCC-4, across different cellular models of prostate cancer drug resistance is performed.Abstract:
The androgen receptor is a major driver of prostate cancer and inhibition of its transcriptional activity using competitive antagonists, such as enzalutamide remains a frontline therapy for prostate cancer management. However, the majority of patients eventually develop drug resistance. We propose that targeting the androgen receptor for degradation via Proteolysis Targeting Chimeras (PROTACs) will be a better therapeutic strategy for targeting androgen receptor signaling in prostate cancer cells. Here we perform a head-to-head comparison between a currently approved androgen receptor antagonist enzalutamide, and its PROTAC derivative, ARCC-4, across different cellular models of prostate cancer drug resistance. ARCC-4 is a low-nanomolar androgen receptor degrader able to degrade about 95% of cellular androgen receptors. ARCC-4 inhibits prostate tumor cell proliferation, degrades clinically relevant androgen receptor point mutants and unlike enzalutamide, retains antiproliferative effect in a high androgen environment. Thus, ARCC-4 exemplifies how protein degradation can address the drug resistance hurdles of enzalutamide.read more
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PROTAC targeted protein degraders: the past is prologue
TL;DR: Targeted protein degradation with proteolysis-targeting chimeras (PROTACs) has the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules as mentioned in this paper .
Journal ArticleDOI
Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery
George M. Burslem,Craig M. Crews +1 more
TL;DR: The burgeoning field of proteolysis-targeting chimeras (PROTACs), which are capable of modulating protein concentrations at a post-translational level by co-opting the ubiquitin-proteasome system, are described and their application to drug discovery is described.
Journal ArticleDOI
PROteolysis TArgeting Chimeras (PROTACs) - Past, Present and Future
TL;DR: Important milestones in the development of the PROTAC technology are addressed, as well as key findings from this previous year are emphasized and future directions of this promising drug discovery modality are highlighted.
Journal ArticleDOI
PROTACs: great opportunities for academia and industry.
TL;DR: Although PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic.
Journal ArticleDOI
Targeted protein degradation: elements of PROTAC design.
Stacey-Lynn Paiva,Craig M. Crews +1 more
TL;DR: This review aims to highlight the recent advances in targeted protein degradation and describe the challenges that need to be addressed in order to efficiently develop potent PROTACs.
References
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Journal ArticleDOI
Abiraterone and Increased Survival in Metastatic Prostate Cancer
Johann S. de Bono,Christopher J. Logothetis,Arturo Molina,Karim Fizazi,Scott North,Luis Chu,Kim N. Chi,Robert Jones,Oscar B. Goodman,Fred Saad,John Staffurth,Paul N. Mainwaring,S. J. Harland,Thomas W. Flaig,Thomas E. Hutson,Tina Cheng,Helen Patterson,John D. Hainsworth,Charles J. Ryan,Cora N. Sternberg,Susan Ellard,Aude Flechon,Mansoor N. Saleh,Mark C. Scholz,Eleni Efstathiou,Andrea Zivi,Diletta Bianchini,Yohann Loriot,Nicole Chieffo,Thian Kheoh,Christopher M. Haqq,Howard I. Scher +31 more
TL;DR: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.
Journal ArticleDOI
Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy
Howard I. Scher,Karim Fizazi,Fred Saad,Mary-Ellen Taplin,Cora N. Sternberg,Kurt Miller,Ronald de Wit,Peter F.A. Mulders,Kim N. Chi,Neal D. Shore,Andrew J. Armstrong,Thomas W. Flaig,Aude Flechon,Paul N. Mainwaring,Mark D. Fleming,John D. Hainsworth,Mohammad Hirmand,Bryan Selby,Lynn Seely,Johann S. de Bono,B Ch +20 more
TL;DR: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.
Journal ArticleDOI
Emerging roles of caspase-3 in apoptosis
Alan G. Porter,Reiner U. Jänicke +1 more
TL;DR: Caspase-3 is essential for certain processes associated with the dismantling of the cell and the formation of apoptotic bodies, but it may also function before or at the stage when commitment to loss of cell viability is made.
Journal ArticleDOI
Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer
Chris Tran,Samedy Ouk,Nicola J. Clegg,Yu Chen,Philip A. Watson,Vivek K. Arora,John Wongvipat,Peter Smith-Jones,Dongwon Yoo,Andrew Kwon,Teresa Wasielewska,Derek S. Welsbie,Charlie D. Chen,Celestia S. Higano,Tomasz M. Beer,David T. Hung,Howard I. Scher,Michael E. Jung,Charles L. Sawyers +18 more
TL;DR: The diarylthiohydantoins RD162 and MDV3100 are characterized, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression that appear to be promising candidates for treatment of advanced prostate cancer.
Journal ArticleDOI
Androgen Receptor in Prostate Cancer
TL;DR: AR remains important in the development and progression of prostate cancer and the inhibition of AR activity through mechanisms in addition to androgen ablation, such as modulation of signal transduction pathways, may delay prostate cancer progression.
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