Fig. 1. Biophysical and structural characterisation of compound 3 and previously disclosed SMARCA bromodomain binders.

a Comparison of previously disclosed SMARCA binders with sub-µM binding affinity: PFI-3¹³, GEN-1¹⁴, “compound 18”¹⁷ and “compound-26”¹⁷. b Optimisation of the halogen bonding interaction to Leu1456 based on an alternative benzoxazinone lead series (light brown, fluorine; green, chlorine; dark brown, bromine; purple, iodine; orange, SMARCA peptide. c SAR of SMARCA binding scaffold with reduced hydrogen bond donor count. d Binding mode and interactions of compound 4 (a close analogue of compound 3) with SMARCA2^BD (PDB: 7Z78). See legend in figure for annotation of colours and symbols. e Superposition of the SMARCA2^BD: compound 4 complex (green) with PDB: 6HAZ (yellow, GEN-1) highlighting key interactions towards Asn1464, Leu1456 and Glu1417. f SPR sensorgrams for binding of compound 3/GEN-1 to SMARCA2^BD; mean values reported with standard deviation (n = 3 independent experiments). Source data are provided as a Source Data file. Colours are different concentrations as indicated.