Fragment-based (FB) and high throughput screening (HTS) methods have been the major contributors to successful drug discovery programs. While most studies utilize one of the methods, a successive combination of two often affords potent hits screening relatively small compound library sets. We have performed a study utilizing advantages of both methods to find potent inhibitors of BRD4.<br/>Initially, we screened a diverse set of 3,695 fragment-like molecules utilizing differential scanning fluorimetry (DSF) and identified 73 confirmed shifters. Analysis of the stock revealed 3,200 drug-like derivatives of the active fragments. A DSF assay of the derivatives of the active fragments, their analogues (3,200 compounds selected by physicochemical profiles), and the derivatives of inactive fragments identified 108 hits (51, 26, and 31, respectively), 61 of which were confirmed by functional assay. The majority of hits with IC50 &lt; 40 µM were from the active derivatives set (9), while those from the analogues and the inactive derivatives were 5 and 4, respectively. The confirmed hit compounds are dissimilar to the known BRD4 inhibitors and have favorable ADMET profiles.

New inhibitors of BRD4 identified by combining fragment-based and HTS approaches

255th National Meeting (2018)

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