SMARCA4 (BRG1), an ATP-dependent helicase, is a subunit of the SWI/SNF chromatin remodeling complex which regulates genes involved in repair of damaged DNA, replication of DNA, control of cell growth, division, and maturation [1]. Considering biological significance of BRG1 we set out to explore the protein with the aim to identify new modulators.

Using Weak Affinity Chromatography (WAC™) as the primary screening method a number of hits for the bromodomain of SMARCA4 were identified. Our ligandability fragment set (250 compounds) was used for the screen – designed to rapidly assess the ability of biological targets to bind small organic molecules.

Subsequent hit validation by DSF (thermal shift assay) afforded confidence in several hits which were progressed into X-ray crystallography. This resulted in four structures of protein-ligand complexes, where two hits bound to the orthosteric site while the other two fragments were found at a new site which, to the best of our knowledge, is not described in the literature.

At this point, the activities were directed towards exploring and characterizing the newly identified binding site by hit clustering, SAR analysis, hit expansion (by SAR-by-catalogue and parallel chemistry) as well as computational chemistry (docking, hit evolution).

[1] Sci. Adv., 2015, 1, 5, e1500447