Protein-protein interactions (PPIs) are important targets for the development of chemical probes and therapeutic agents. From the initial discovery of the existence of hot spots at PPI interfaces, it has been proposed that hot spots might provide the key for developing small-molecule PPI inhibitors. However, there has been no review on the ways in which the knowledge of hot spots can be used to achieve inhibitor design, nor critical examination of successful examples. This Digest discusses the characteristics of hot spots and the identification of druggable hot spot pockets. An analysis of four examples of hot spot-based design reveals the importance of this strategy in discovering potent and selective PPI inhibitors. A general procedure for hot spot-based design of PPI inhibitors is outlined.
Structure-based optimization was conducted to improve the potency, selectivity, and cell-based activities of β-catenin/B-cell lymphoma 9 (BCL9) inhibitors based on the 4'-fluoro- N-phenyl-[1,1'-biphenyl]-3-carboxamide scaffold, which was designed to mimic the side chains of the hydrophobic α-helical hot spots at positions i, i + 3, and i + 7. Compound 29 was found to disrupt the β-catenin/BCL9 protein-protein interaction (PPI) with a K of 0.47 μM and >1900-fold selectivity for β-catenin/BCL9 over β-catenin/E-cadherin PPIs. The proposed binding mode of new inhibitors was consistent with the results of site-directed mutagenesis and structure-activity relationship studies. Cell-based studies indicated that 29 disrupted the β-catenin/BCL9 interaction without affecting the β-catenin/E-cadherin interaction, selectively suppressed transactivation of Wnt/β-catenin signaling, downregulated expression of Wnt target genes, and inhibited viability of Wnt/β-catenin-dependent cancer cells in dose-dependent manners. A comparison of the biochemical and cell-based assay results offered the directions for future inhibitor optimization.
The cross-coupling of alkyl cyanamides with a number of aryl, heteroaryl, and vinyl halide and pseudohalide coupling partners has been developed via a modification of Pd-catalyzed amidation methods. The reactions proceed selectively under mild conditions with reasonable reaction times in moderate to excellent yields.
The
“butterfly-shaped” bicyclic pyrrolidinol ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)-methanol (1)
is a key building block for drug candidates, and its practical chemical
synthesis remains elusive. As such, an asymmetric synthesis for ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)-methanol (1)
that is amenable for scale-up has been developed. The newly optimized
process utilizes readily available N-Boc-trans-4-hydroxy-l-proline methyl ester (8) to establish the challenging stereogenic center bearing the fluoride.
Subsequent diastereoselective α-alkylation was achieved by leveraging
Seebach’s self-regeneration of stereochemistry (SRS) methodology,
which has been exploited for the synthesis of proline derivatives.
Finally, intramolecular cyclization/deprotection cascade and carbonyl
reduction afford the bicyclic pyrrolidinol 1 in nine
linear steps from compound 8. This process significantly
reduces the overall production sequence and allows the preparation
of product 1 on a multikilo scale with a 40% overall
yield and perfect control of chirality (>99% ee and de).
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