Drug Discovery Approaches to Target E3 Ligases.

Targeting E3 ligases is a challenging area in drug discovery. Despite the human genome encoding for more than 600 E3 ubiquitin ligases, only a handful of E3 ligases have been pharmacologically modulated or exploited for targeted protein degradation (TPD) strategies. The main obstacle for hijacking these E3 ligases is the lack of small-molecule ligands.

Pharmacological potentiators of the calcium signaling cascade identified by high-throughput screening.

Pharmacological modulators of the Ca signaling cascade are important research tools and may translate into novel therapeutic strategies for a series of human diseases. We carried out a screening of a maximally diverse chemical library using the Ca-sensitive Cl channel TMEM16A as a functional readout. We found compounds that were able to potentiate UTP-dependent TMEM16A activation.

Comprehensive Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology.

Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies.

Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel.

F508del, the most frequent mutation causing cystic fibrosis (CF), results in mistrafficking and premature degradation of the CFTR chloride channel. Small molecules named correctors may rescue F508del-CFTR and therefore represent promising drugs to target the basic defect in CF. We screened a carefully designed chemical library to find F508del-CFTR correctors.

Gold(I)-catalysed cascade reactions in the synthesis of 2,3-fused indole derivatives.

A gold(I)-catalysed hydroaminative/arylative cascade for the efficient synthesis of a variety of indole-fused skeletons has been developed. Factors controlling the catalyst loading required in these transformations involving 1,3-unsubstituted indole intermediates have been revealed, allowing isolation of an unprecedented 1,3-dimetallated 3H-indole gold complex characterized by X-ray diffraction.

FeCl3·6H2O-catalyzed Mukaiyama-aldol type reactions of enolizable aldehydes and acetals.

Mukaiyama-aldol type reactions of acetals derived from enolizable aldehydes with FeCl3·6H2O, an eco-friendly, low-cost, and stable catalyst, lead to β-methoxycarbonyl compounds with nearly quantitative yields. The methodology is extended to the parent aldehydes as starting materials, leading to the corresponding aldols with lower yields, but efficiently. Different alkyl and aryl substituted acetals and aldehydes have been tested in the reaction with linear and cyclic silyl enol ethers.

A new family of "clicked" estradiol-based low-molecular-weight gelators having highly symmetry-dependent gelation ability.

Reported herein is the discovery of a novel family of "clicked" estradiol-based LMWGs whose gelation ability highly depends on the gelator symmetry. These LMWGs that gel different organic solvents in the presence of H(2)O even at concentrations as low as 0.04 wt% are readily accessible using "click" chemistry.

Direct assembly of polyarenes via C-C coupling Using PIFA/BF3·Et2O.

Direct oxidative Kita-type coupling between naphthalene and substituted benzenes was found to proceed via four-component coupling, leading to a linear tetraarene with a binaphthalene core. The methodology was extendable to the coupling of unfunctionalized 1,1'-binaphthalene with mesitylene to give a linear hexaarene product in a remarkably chemoselective manner in 87% yield. The method represents an attractive alternative to the traditional syntheses of related oligonaphthalene products via a sequence of metal-catalyzed cross-coupling steps.