Doubling down on BET inhibition-BET抑制剂多价态药物设计

小刚刚

Through simultaneous binding to more than one site in a single protein, multivalent small molecules can achieve huge increases in potency. This ‘avidity effect’ has been demonstrated in BEbeT bromodomain-containing proteins with bivalent probes that represent some of the most potent BET inhibitors to date.
Multivalent small molecules are frequently exploited in Nature’s larger protein–protein interactions, in which many weak interactions, spread over multiple interaction sites, lead to exceptionally potent net overall binding of host and guest. The potential for small-molecule drugs to be multivalent is governed by the number of proteins that offer multiple, druggable binding sites of sufficient proximity that they can be spanned by a molecule that remains within the realm of drug-like space.
In this article, from the laboratories of Bradner and Waring, two small molecules (known as MT1 and biBET, respectively) illustrate that the first and second bromodomains of the BET family can be simultaneously engaged by a single molecule to great effect. The phenomenal potency of the molecules brought about robust and novel effects at significantly lower doses than for monovalent BET chemical probes, while also increasing the selectivity window over off-targets.

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