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Published on: June 23, 2023
Structural and Biophysical Characterization of Aminobenzo[d]isothiazole 1,1-Dioxide SOS1 Ligands
Thiago Moreira Pereira1,2, Atilio Reyes Romero1,2, Marleen van der Laan3
1Regional Centre of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute (CATRIN), Palacký University Olomouc, Šlechtitelů 27, Olomouc, 783 71, Czech Republic.
None:
SOS1 is a guanine nucleotide exchange factor that promotes KRAS activation by catalyzing GDP release and GTP loading, making SOS1-mediated nucleotide exchange an attractive therapeutic target in KRAS-driven cancers. Herein, we report the synthesis, biophysical characterization, and structural analysis of aminobenzo-[d]-isothiazole 1,1-dioxide SOS1 ligands. Compound 6f engaged SOS1 with a KD of 570 nM by microscale thermophoresis, supported by surface plasmon resonance. X-ray crystal structures of SOS1 bound to compounds 6b and 6f refined previous binding hypotheses regarding pocket engagement. Rather than being dominated by sulfone-mediated contacts, SOS1 recognition is primarily driven by hydrophobic and aromatic packing within the canonical pocket, a conserved ligand NH hydrogen bond to Asn879, and π-π stacking with Tyr884, recapitulating key features of BI-3406 binding. Comparative analysis further delineates vector requirements for productive engagement of KRAS-facing regions, providing a structure-based framework for future optimization of aminobenzo-[d]-isothiazole 1,1-dioxide SOS1 ligands.
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