In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38α MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38α MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography.

Misregulation and mutations of the transcription factor Nrf2 are involved in the development of a variety of human diseases. In this study, we employed the technology of stapled peptides to address a protein-DNA-complex and designed a set of Nrf2-based derivatives. Varying the length and position of the hydrocarbon staple, we chose the best peptide for further evaluation in both fixed and living cells. Peptide 4 revealed significant enrichment within the nucleus compared to its linear counterpart 5, indicating potent binding to DNA. Our studies suggest that these molecules offer an interesting strategy to target activated Nrf2 in cancer cells.

Transcription factors (TFs) constitute a diverse class of sequence-specific DNA-binding proteins, which are key to the modulation of gene expression. TFs have been associated with human diseases, including cancer, Alzheimer's and other neurodegenerative diseases, which makes this class of proteins attractive targets for chemical biology and medicinal chemistry research. Since TFs lack a common binding site or structural similarity, the development of small molecules to efficiently modulate TF biology in cells and is a challenging task. This review highlights various strategies that are currently being explored for the identification and development of modulators of Myc, p53, Stat, Nrf2, CREB, ER, AR, HIF, NF-κB, and BET proteins.

The syntheses are reported of the 1,1,5-trimethyl-2,8-dioxa-5-aza-1-stannabicyclo[3.3.0]octane MeN(CH2CH2O)2SnMe2 (1), its monosodium aminoalcoholate adduct [MeN(CH2CH2O)2SnMe2·MeN(CH2CH2ONa)(CH2CH2OH)]2 (2), and the hexanuclear organotin oxo cluster [MeN(CH2CH2O)2SnMe2·Me2SnO]3 (3). The compounds were characterized by 1H, 13C, and 119Sn NMR spectroscopy, electrospray ionization mass spectrometry, and single-crystal X-ray diffraction analysis. In the solid state, compound 1 is a tetramer that is brought about by intermolecular O→Sn interactions. In solution, however, it shows a monomer ⇌ dimer equilibrium that is fast on the 1H, 13C, and 119Sn NMR time scales at room temperature. All compounds show intramolecular N→Sn interactions at Sn–N distances ranging between 2.378(3) Å (2) and 3.026(3) Å (3·0.25H2O). Compound 3 can formally be regarded as a molecular dimethyltin oxide being trapped by head-to-tail complexation with a stannabicyclooctane. In solution, it slowly falls apart into 1 and Me2SnO.