Journal ArticleDOI
Design, synthesis and selection of DNA-encoded small-molecule libraries
Matthew A. Clark,Raksha A. Acharya,Christopher C. Arico-Muendel,Svetlana L. Belyanskaya,Dennis Benjamin,Neil R Carlson,Paolo A. Centrella,Cynthia H. Chiu,Steffen Phillip Creaser,John W. Cuozzo,Christopher P. Davie,Yun Ding,G Joseph Franklin,Kurt D Franzen,Malcolm L. Gefter,Steven P Hale,Nils Jakob Vest Hansen,David I. Israel,Jinwei Jiang,Malcolm J. Kavarana,Michael Kelley,Christopher S. Kollmann,Fan Li,Kenneth E Lind,Sibongile Mataruse,Patricia F Medeiros,Jeffrey A. Messer,Paul Myers,Heather O’Keefe,Matthew C Oliff,Cecil E Rise,Alexander L. Satz,Steven R. Skinner,Jennifer L Svendsen,Lujia Tang,Kurt van Vloten,Richard W. Wagner,Gang Yao,Baoguang Zhao,Barry A. Morgan +39 more
TLDR
An 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide is reported, assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection.Abstract:
Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.read more
Citations
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Journal ArticleDOI
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
TL;DR: Major improvements to the proteolysis targeting chimeras (PROTACs) method are described, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation.
Journal ArticleDOI
Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation
Huw D. Lewis,John Liddle,Jim E Coote,Stephen John Atkinson,Michael David Barker,Benjamin D. Bax,Kevin L. Bicker,Ryan P. Bingham,Matthew Campbell,Yu Hua Chen,Chun-wa Chung,Peter D. Craggs,Robert P. Davis,Dirk Eberhard,Gerard Joberty,Kenneth E Lind,Kelly Locke,Claire Maller,Kimberly Martinod,Chris Patten,Oxana Polyakova,Cecil E Rise,Martin Rüdiger,Robert J. Sheppard,Daniel J. Slade,Pamela Thomas,Jim Thorpe,Gang Yao,Gerard Drewes,Denisa D. Wagner,Paul R. Thompson,Rab K. Prinjha,David Matthew Wilson +32 more
TL;DR: Novel, selective PAD4 inhibitors binding to a calcium-deficient form of the PAD3 enzyme have been validated, for the first time, in both histone citrullination and neutrophil extracellular trap formation, validating the critical enzymatic role of human and mouse PAD 4.
Journal ArticleDOI
Quorum sensing
TL;DR: When the Hawaiian bobtail squid rises from the sand each evening to hunt, it swims cloaked from detection by predators and prey because it casts no moonlight shadow, a trick it owes to compartments full of glowing bacteria on its underside.
Journal ArticleDOI
DNA-encoded chemistry: enabling the deeper sampling of chemical space
TL;DR: This Review provides an overview of the development and applications of DNA-encoded chemistry, highlighting the challenges and future directions for the use of this technology.
Journal ArticleDOI
Aurora A kinase (AURKA) in normal and pathological cell division.
TL;DR: The mitotic and non-mitotic functions of Aurora A are reviewed, Aurora A regulation in the context of protein structural information is discussed, and progress in understanding and inhibiting Aurora A in cancer is evaluated.
References
More filters
Journal ArticleDOI
Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase
Craig Tuerk,Larry Gold +1 more
TL;DR: High-affinity nucleic acid ligands for a protein were isolated by a procedure that depends on alternate cycles of ligand selection from pools of variant sequences and amplification of the bound species.
Journal ArticleDOI
In vitro selection of RNA molecules that bind specific ligands.
TL;DR: Subpopulations of RNA molecules that bind specifically to a variety of organic dyes have been isolated from a population of random sequence RNA molecules.
Journal ArticleDOI
Genome sequencing in microfabricated high-density picolitre reactors
Marcel Margulies,Michael Egholm,William E. Altman,Said Attiya,Joel S. Bader,Lisa A. Bemben,Jan Berka,Michael S. Braverman,Yi-Ju Chen,Zhoutao Chen,Scott Dewell,Lei Du,J. M. Fierro,Xavier V. Gomes,Brian C. Godwin,Wen He,Scott Edward Helgesen,Chun Heen Ho,Gerard P. Irzyk,Szilveszter C. Jando,Maria L. I. Alenquer,Thomas P. Jarvie,Kshama B. Jirage,Jong-Bum Kim,James R. Knight,Janna R. Lanza,John H. Leamon,Steven Lefkowitz,Ming Lei,Jing Li,Kenton Lohman,Hong Lu,Vinod Makhijani,Keith Mcdade,Michael P. McKenna,Eugene W. Myers,Elizabeth Nickerson,John Nobile,Ramona Plant,Bernard P. Puc,Michael T. Ronan,George T. Roth,Gary J. Sarkis,Jan Fredrik Simons,John Simpson,Maithreyan Srinivasan,Karrie R. Tartaro,Alexander Tomasz,Kari A. Vogt,Greg A. Volkmer,Shally H. Wang,Yong Wang,Michael P. Weiner,Pengguang Yu,Richard F. Begley,Jonathan M. Rothberg +55 more
TL;DR: A scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments with 96% coverage at 99.96% accuracy in one run of the machine is described.
Journal ArticleDOI
Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface
TL;DR: Foreign DNA fragments can be inserted into filamentous phage gene III to create a fusion protein with the foreign sequence in the middle that is incorporated into the virion, which retains infectivity and displays the foreign amino acids in immunologically accessible form.
Journal ArticleDOI
VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo
Elizabeth A Harrington,David Bebbington,Jeff Moore,Richele K Rasmussen,Abi O Ajose-Adeogun,Tomoko Nakayama,Joanne A Graham,Cecile Demur,Thierry Hercend,Thierry Hercend,Anita Diu-Hercend,Anita Diu-Hercend,Michael Su,Golec Julian M C,Karen Miller +14 more
TL;DR: A highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses.