Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
TLDR
Induced protein degradation has the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.Abstract:
Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.read more
Citations
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Structural basis of PROTAC cooperative recognition for selective protein degradation.
M.S. Gadd,Andrea Testa,Xavier Lucas,Kwok-Ho Chan,Wenzhang Chen,Douglas J. Lamont,Michael Zengerle,Alessio Ciulli +7 more
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References
More filters
Journal ArticleDOI
Bicalutamide (Casodex®) in the treatment of prostate cancer: History of clinical development
TL;DR: Clinical trials are currently in progress to further evaluate bicalutamide as monotherapy in patients with advanced stages of disease and as adjuvant or first‐line therapy in patientswith early‐stage disease.
Journal ArticleDOI
A protein knockdown strategy to study the function of β-catenin in tumorigenesis
TL;DR: The protein knockdown strategy can be utilized not only as a novel method to dissect the role of oncoproteins in tumorigenesis, but also as a unique tool to delineate the function of a subpopulation of proteins localized to a specific subcellular compartment.
Journal ArticleDOI
Chemical Biology Strategies for Posttranslational Control of Protein Function
TL;DR: Recent advances in technologies for conditional regulation of protein function are reviewed and further areas of potential development are suggested.
Journal ArticleDOI
Synthesis and evaluation of geldanamycin–testosterone hybrids
Scott D. Kuduk,Christina Harris,Fuzhong F. Zheng,Laura Sepp-Lorenzino,Quathek Ouerfelli,Neal Rosen,Samuel J. Danishefsky,Samuel J. Danishefsky +7 more
TL;DR: A series of GDM-testosterone linked hybrids has been synthesized and evaluated for activity against prostate cancer cell lines and the hybrid with the greatest activity exhibits potent and selective cytotoxicityagainst prostate cancer cells containing the androgen receptor.
Journal ArticleDOI
Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy.
Yosuke Demizu,Keiichiro Okuhira,Hiromi Motoi,Akiko Ohno,Takuji Shoda,Kiyoshi Fukuhara,Haruhiro Okuda,Mikihiko Naito,Masaaki Kurihara +8 more
TL;DR: Three estrogen receptor degradation inducers are designed and synthesized, which crosslink the ER and the cellular inhibitor of apoptosis protein 1 (cIAP1) resulting in its proteasomal degradation.
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