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
Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity.
Hao Wu,Ka Yang,Zhongrui Zhang,Eric D Leisten,Ziyuan Li,Haibo Xie,Jin Liu,Kerry A. Smith,Zora Novakova,Cyril Barinka,Weiping Tang +10 more
TL;DR: A new generation of multi-functional HDAC6 degraders by tethering selectiveHDAC6 inhibitor Next-A with CRBN ligand that can synergize with HDAC 6 degradation for the anti-proliferation of multiple myeloma is reported.
Journal ArticleDOI
Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation.
Nobumichi Ohoka,Yoko Morita,Katsunori Nagai,Kenichiro Shimokawa,Osamu Ujikawa,Ikuo Fujimori,Masahiro Ito,Youji Hayase,Keiichiro Okuhira,Norihito Shibata,Takayuki Hattori,Tomoya Sameshima,Osamu Sano,Ryokichi Koyama,Yasuhiro Imaeda,Hiroshi Nara,Nobuo Cho,Mikihiko Naito +17 more
TL;DR: It is reported that derivatization of the IAP ligand module yields SNIPER(ER)s with superior protein-knockdown activity, andMechanistic analysis revealed that the novel SNIPer( ER)s preferentially recruit XIAP, rather than cIAP1, to degrade ERα.
Journal ArticleDOI
Development of Stabilized Peptide-Based PROTACs against Estrogen Receptor α
Yanhong Jiang,Qiwen Deng,Hui Zhao,Mingsheng Xie,Longjian Chen,Feng Yin,Xuan Qin,Weihao Zheng,Yong Juan Zhao,Zigang Li +9 more
TL;DR: This work is a successful attempt to construct PROTACs based on cell-permeable stabilized peptides, which significantly broadens the chemical space ofprotACs and stabilized peptided.
Journal ArticleDOI
Developing potent PROTACs tools for selective degradation of HDAC6 protein
TL;DR: The newly designed PROTACs induced significant degradation of HDAC6 in a panel of cell lines, exhibited excellent selectivity against other HDACs, and demonstrated efficient inhibition of cell proliferation.
Journal ArticleDOI
VHL and Hypoxia Signaling: Beyond HIF in Cancer
Jing Zhang,Qing Zhang +1 more
TL;DR: This review will focus on VHL-mediated signaling pathways involving the latest identified substrates/binding partners, including N-Myc downstream-regulated gene 3 (NDRG3), AKT, and G9a, etc., and their physiological roles in hypoxia signaling and cancer.
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