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.
Abstract
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.
It is demonstrated that the AlphaFold-guided free energy calculations can capture experimentally observed substrate and inhibitor trends in PH-06 PRM, while identifying a remote ligand-binding pocket that warrants further mechanistic investigation.
Yishai Gilron, Jose Manuel Diaz Antunes, Devi Kumari Dhakal Gaudel et al.· Journal of Chemical Informat...· 0 citations
G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in the regulation of key biological processes and represent attractive targets for therapeutic intervention. In this study, we report the design, synthesis, and biophysical evaluation of a new family of water-soluble heptacyclic oligo-heteroaryl lig...
Giorgia Fracchioni, A. M. Caramiello, M. Nadai et al.· ACS Omega· 0 citations
AIMS
To synthesize and evaluate a series of thiosemicarbazone derivatives (2a-2g) incorporating thiophene-2-carboxylic acid as urease inhibitors.
MATERIALS AND METHODS
The compounds were synthesized and characterized using modern spectroscopic techniques. In vitro urease inhibition was determined followed by computat...
W. Khan, Laiba, Imtiaz Ahmad et al.· Future Medicinal Chemistry· 0 citations
Covalent probes and therapeutics must balance electrophilicity and stability for function in biological systems, yet gains in stability can sacrifice proteome coverage and limit ligand discovery. Here, we show that single-atom N-to-C substitutions of sulfonyl purines at the nucleofuge position decouple reactivity fro...
Zhihong Li, Madeleine L. Ware, Phillip W. Gingrich et al.· Journal of the American Chem...· 0 citations
A robust design for αVβ6-targeting functional probes for molecular imaging and fluorescence-guided tumor detection and an anthracenyl-functionalized derivative combines sub-nanomolar αVβ6 affinity with water solubility and intrinsic fluorescence, demonstrating that even bulky π-systems can be accommodated at discrete p...
Beate Nachtigall, Caroline Brinkmann, J. Langosch et al.· Chemistry· 0 citations
Nine mechanochemically prepared 4′-(N,N-dimethylamino)azobenzene-n-carboxamides (n = 2–4) derived from α-amino acid esters were structurally characterized. X-ray diffraction on single crystals of chiral amides reveals a notably high incidence of structures with Z′ > 1 (five out of eight). Structural analysis indicate...
Alen Bjelopetrović, Sara Morasi Piperčić, Marina Juribašić Kulcsár· Crystal Growth & Design· 0 citations
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