Development of BET inhibitors as potential treatments for cancer: A search for structural diversity
Matthew D Hill1, Haiquan Fang1, John Tokarski1
1Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
Abstract:
We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.
More Related Videos
Related Concept Videos
Targeted Cancer Therapies
There are several types of targeted therapies against...
Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
Inhibition of Cdk Activity
Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Drugs that Stabilize Microtubules
Drugs that Destabilize Microtubules


