Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
Reads0
Chats0
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
More filters
Journal ArticleDOI
Structural basis of PROTAC cooperative recognition for selective protein degradation.
M.S. Gadd,Andrea Testa,Xavier Lucas,Kwok-Ho Chan,Wenzhang Chen,Douglas J. Lamont,Michael Zengerle,Alessio Ciulli +7 more
TL;DR: The results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.
Journal ArticleDOI
Kinase inhibitors: the road ahead
TL;DR: An overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors are provided.
Journal ArticleDOI
Drugging the 'undruggable' cancer targets
TL;DR: Four scientists working in the 'undruggable' cancer research field are asked for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of research.
Journal ArticleDOI
Targeting transcription factors in cancer - from undruggable to reality.
TL;DR: This Review discusses the various approaches that are being explored to target transcription factors in cancer, with many of the inhibitors developed from such approaches now advancing to early clinical trials.
Journal ArticleDOI
Expanding the medicinal chemistry synthetic toolbox
TL;DR: Opportunities for the expansion of the medicinal chemists' synthetic toolbox are highlighted to enable enhanced impact of new methodologies in future drug discovery.
References
More filters
Journal ArticleDOI
Development of Small Molecules Targeting the Pseudokinase Her3
Sang Min Lim,Ting Xie,Kenneth D. Westover,Scott B. Ficarro,Hyun Seop Tae,Deepak Gurbani,Taebo Sim,Jarrod A. Marto,Pasi A. Jänne,Craig M. Crews,Nathanael S. Gray +10 more
TL;DR: The structure-based medicinal chemistry effort that resulted in the discovery of the first selective irreversible Her3 ligand that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases is reported on.
Journal ArticleDOI
Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination *
TL;DR: Structural analysis and molecular dynamics simulations based on Cul1, Cul4A, and Cul5 crystal structures show that these three cullins are not rigid scaffolds but are flexible with conserved hinges in the N-terminal domain, however, the degrees of flexibilities are distinct among the different cullins.
Journal ArticleDOI
Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer.
Robert Hugh Bradbury,Neil James Hales,Alfred A. Rabow,Graeme Walker,David G. Acton,David M. Andrews,Peter Ballard,Nigel Brooks,Nicola Colclough,Alan Girdwood,Urs Hancox,Owen Jones,David A. Jude,Sarah A. Loddick,Andrew A. Mortlock +14 more
TL;DR: A medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.
Journal ArticleDOI
Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer
Robert Hugh Bradbury,David G. Acton,Nicola Broadbent,A. Nigel Brooks,Carr Gregory Richard,Glenn Hatter,Barry R. Hayter,Hill Kathryn Jane,Nicholas J. Howe,Rhys D.O. Jones,David A. Jude,Scott G. Lamont,Sarah A. Loddick,Heather L. McFarland,Zaieda Parveen,Alfred A. Rabow,Gorkhn Sharma-Singh,Natalie Stratton,Andrew G. Thomason,Dawn Trueman,Graeme Walker,Stuart L. Wells,Joanne Wilson,J. Matthew Wood +23 more
TL;DR: Clinical candidate 6-(4-{4-[2-acetylpiperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Journal Article
Fulvestrant in Postmenopausal Women with Advanced Breast Cancer
Peter F. Bross,Amy Baird,Gang Chen,Josephine M. Jee,Richard T. Lostritto,David E. Morse,Liliam A. Rosario,Gene M. Williams,Peiling Yang,Atiqur Rahman,Grant R. Williams,Richard Pazdur +11 more
TL;DR: The data and analyses supporting marketing approval for FVT are described, which were approved on April 25, 2002 by the FDA for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy.
Related Papers (5)
Catalytic in vivo protein knockdown by small-molecule PROTACs
Daniel P. Bondeson,Alina Mares,Ian Edward David Smith,Ko Eunhwa,Sebastien Andre Campos,Afjal Hussain Miah,Katie E Mulholland,Natasha Routly,Dennis L. Buckley,Jeffrey L. Gustafson,Nico Zinn,Paola Grandi,Satoko Shimamura,Giovanna Bergamini,Maria Faelth-Savitski,Marcus Bantscheff,Carly S. Cox,Deborah A. Gordon,Ryan R. Willard,John J. Flanagan,Linda N. Casillas,Bartholomew J. Votta,Willem den Besten,Kristoffer Famm,Laurens Kruidenier,Paul S. Carter,John D. Harling,Ian Churcher,Craig M. Crews +28 more