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8
result(s) for
"Waring, Geoff"
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Oscar and the cricket : a book about moving and rolling
Cricket shows Oscar the kitten how various objects need a push or a pull to move but animals can move themselves by using their muscles.
Book
Oscar and the snail : a book about things we use
When Oscar the kitten comes across a nest made of twigs and leaves, Snail explains why specific materials are chosen to do different jobs, where the materials come from, and what useful qualities they have.
Book
SMALLTALK Business Marketplace
Small businesses often earn low returns. Yet I have seen companies that cater to the poorest customers, or which do business in the least trendy industries, earn extremely high returns. Why? They see a chance where no-one else does, so competition is minimal and customers are appreciative.
Newspaper Article
Potent and selective bivalent inhibitors of BET bromodomains
Structural insights demonstrating small-molecule-mediated dimerization of BRD4 bromodomains led to the development of biBET, a compound that potently inhibits BRD4–acetyl-lysine interactions by bivalent binding to tandem bromodomains.
Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent,
in cis
binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4–mediator complex subunit 1 foci with an EC
50
of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design—simultaneous targeting of two separate domains with a drug-like small molecule—providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.
Journal Article
