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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Journal ArticleDOI
Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex.
Mingyu Wang,Rongkun Lin,Jia-cheng Li,Yuying Suo,Jing Gao,Liping Liu,Liyuan Zhou,Yicheng Ni,Ziqun Yang,Jie Zheng,Jin Lin,Huancheng Zhou,Cheng Luo,Hua-Ching Lin +13 more
TL;DR: In this article , a series of hydrophobic tagging-based degraders of the CDK8-cyclin C complex were designed, synthesized, and evaluated to identify the first dual degrader, LL-K 8-22, which induced selective and synchronous degradation of CDK 8 and cyclin C.
Patent
Inhibitors of rna-guided nuclease target binding and uses thereof
TL;DR: Compositions and methods for inhibiting the activity of RNA-guided endonucleases are discussed in this article, as well as treatment using the inhibitory compounds, formulations and methods.
Journal ArticleDOI
Photocontrollable PROTAC molecules: Structure and mechanism of action
TL;DR: By merging the principles of photopharmacology and PROTAC technology, photocontrollable PROTACs for spatiotemporal control of induced protein degradation have recently emerged and their main advantage is the possible prevention of off-target toxicity thanks to local photoactivation.
Journal ArticleDOI
Discovery of Norbornene as a Novel Hydrophobic Tag Applied in Protein Degradation
TL;DR: In this article , the authors used hydrophobic tagging to degrade the anaplastic lymphoma kinase (ALK) fusion protein by linking it to ALK inhibitors and showed a significant tumor-inhibiting effect in vivo with moderate oral bioavailability.
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Hallmarks of Anaplastic Lymphoma Kinase Inhibitors with Its Quick Emergence of Drug Resistance
TL;DR: Anaplastic lymphoma kinase (ALK) is one of the most popular targets for anticancer therapies as mentioned in this paper , however, resistance mechanisms of ALK-targeted therapies initially benefit the patients, yet, resistance eventually occurs.
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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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