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
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Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy
TL;DR: In this paper , the authors focus on the current efforts in the discovery and development of various orally available anti-cancer PROTAC degraders, and comprehensively summarize the strategies applied to this end.
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Beute für das Proteasom: Gezielter Proteinabbau aus medizinalchemischer Perspektive
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Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation
Hidetomo Yokoo,Nobumichi Ohoka,Mami Takyo,Takahito Ito,Keisuke Tsuchiya,Takashi Kurohara,Kiyoshi Fukuhara,Takao Inoue,Mikihiko Naito,Yosuke Demizu +9 more
TL;DR: The stapled peptide stPERML-R7 as discussed by the authors, which is based on the estrogen receptor alpha (ERα)-binding peptide PERML and composed of natural amino acids, showed increased α-helicity and similar binding affinity toward ERα.
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Preclinical evaluation of proteolytic targeting of LCK as a therapeutic approach in T cell acute lymphoblastic leukemia
Jianzhong Hu,Jamie Jarusiewicz,Guoqing Du,Gisele Nishiguchi,Satoshi Yoshimura,John C. Panetta,Zhenhua Li,Jaeki Min,Lei Yang,Divyabharathi Chepyala,Marisa Actis,Noemi Reyes,Brandon Smart,Ching-Hon Pui,David T. Teachey,Zoran Rankovic,Jun Yang +16 more
TL;DR: Dasatinib-based phenyl-glutarimide PROTACs are promising therapeutic agents in T-ALL and valuable tools for developing degradation-based therapeutics for other cancers.
Journal ArticleDOI
Targeting androgen receptor degradation with PROTACs from bench to bedside.
Xiao-dan Jia,Xin Han +1 more
TL;DR: In the last two decades, potent and efficacious PROTAC AR degraders have been gotten rapid development and several such compounds have been advanced into preclinical phase and phase I/II trials for the treatment of human prostate cancers as discussed by the authors .
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TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
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