MST Delivers Exclusive Hits in Fragment-Based Screening Campaigns

A new study by Boehringer Ingelheim shows that MST is particularly well suited for fragment-based screening and delivers exclusive hits. 29 positives were identified solely by this technology, from which 14 co-crystal structures could be obtained.

The aim of this study was to develop an inhibitor compound targeting the bromodomain of BRD9 (BRD9 BD) within the SWI/SNF chromatin remodeling complex, which is recurrently mutated in tumors. Based on a new scaffold arising from two previous screening approaches, a potent and selective BRD9 BD inhibitor series could be generated. Three parallel biophysical assays, a differential scanning fluorimetry (DSF) assay, a surface plasmon resonance (SPR) assay, and a MicroScale Thermophoresis (MST) assay, were used to screen around 1700 compounds against the BRD9 BD.

The primary screening using MST yielded 38 hits validated by NMR, from which 29 were identified solely by this technology, and from which 14 co-crystal structures could be obtained. Although there was only a 10 % overlap in the primary SPR, DSF and MST hits, this study emphasizes the significant value of pursuing single-technology positives.

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