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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Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy
Jing Gao,Bo Hou,Qiwen Zhu,Lei Yang,Xingyu Jiang,Zhifeng Zou,Xutong Li,Tianfeng Xu,Mingyue Zheng,Yi-Hung Chen,Zhiai Xu,Hui-Xiong Xu,Haijun Yu +12 more
TL;DR: In this paper , a de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation is presented, which self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment.
Journal ArticleDOI
Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation.
Jing Zhang,Fu Liqiang,Bin Shen,Yingtao Liu,Wenqian Wang,Xin Cai,Linglong Kong,Yilin Yan,Ryan Meng,Zhuming Zhang,Ying-Nan P. Chen,Liu Qian,Zhao-Kui Wan,Tianyuan Zhou,Xiaotao Wang,Paul Gavine,Amanda Del Rosario,Kay Ahn,Ulrike Philippar,Ricardo Attar,Jennifer Yang,Xu Yanping,James P. Edwards,Dai Xuedong +23 more
TL;DR: IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.
Journal ArticleDOI
Targeted Protein Degradation through Cytosolic Delivery of Monobody Binders Using Bacterial Toxins
TL;DR: This work provides a prime example of the delivery of a stoichiometric protein inhibitor of an endogenous target protein to cells and inducing its degradation without the need of genetic manipulation of target cells, and lays the foundation for further in vivo exploitation of this delivery system.
Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition
Mikko Taipale,Irina Krykbaeva,Martina Koeva,Can Kayatekin,Kenneth D. Westover,Georgios I. Karras,Susan Lindquist,Susan Lindquist +7 more
TL;DR: The results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family.
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Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Inhibition: An Emerging Strategy in Cancer Therapy
TL;DR: The biological function and modulating network of Nrf2 is described, its oncogenic role is stressed, and possible ways to inhibit NRF2 are pointed out, as well as summarize the reported Nrf 2 inhibitors.
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