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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Bioorthogonal PROTAC Prodrugs Enabled by On-Target Activation.
TL;DR: In this article , a bioorthogonal on-demand prodrug strategy (termed click-release "crPROTACs") was developed to enable on-target activation of PROTAC prodrugs and release of PROTACTs in cancer cells selectively.
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Microneedle Patch Delivery of PROTACs for Anti-Cancer Therapy.
Xiao Cheng,Shiqi Hu,Ke-Wen Cheng +2 more
TL;DR: In this paper , a pH-sensitive micelle, MPEG-poly(β-amino ester) (MPEG-PAE), is used to encapsulate ERD308 along with an FDA-approved CDK4/6 inhibitor, Palbociclib (Pal), before loading into biodegradable microneedle patches.
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The current state of drug repurposing and rare diseases: an interview with Paul Trippier
TL;DR: Paul Tripper is an Associate Professor of Medicinal Chemistry at the University of Nebraska Medical Center (UNMC, NE, USA) and an Editorial Board member of Future Drug Discovery.
Journal ArticleDOI
Targeting hepatitis B virus cccDNA levels: recent progress in seeking small molecule drug candidates.
Yu Jin,Shuang Wang,Shujing Xu,Shujie Zhao,Xiangrui Xu,Vasanthanathan Poongavanam,Luis Menéndez-Arias,Peng Zhan,Xinyong Liu +8 more
TL;DR: In this article , the authors summarized the discovery and optimization of small molecules that target covalently closed circular DNA (cccDNA) synthesis and degradation, including cccDNA synthesis inhibitors, ccc DNA reducers, core protein allosteric modulators, ribonuclease H inhibitors and HBx inhibitors.
Journal ArticleDOI
Recent developments in the Medicinal Chemistry and therapeutic potential of anti-cancer Protacs based molecules.
TL;DR: A comprehensive overview of the current development of PROTACs based anticancer compounds along with the structure-activity relationship of the reported molecules is given to understand the logical design of more efficacious PROTACS based molecules with less toxicity and more selectivity.
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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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