Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.

By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors.

Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1.

TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target, but no small-molecule inhibitors have been published for this challenging interface. Herein, the structure-enabled design and synthesis of a constrained peptide inhibitor of TLE1 is reported.

Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.

The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods.

Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B.

The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 (BAZ2-ICR) of the BAZ2A/B bromodomains through rapid optimization of a weakly potent starting point. A key feature of the presented inhibitors is an intramolecular aromatic stacking interaction that efficiently occupies the shallow bromodomain pockets.

Stereoselective preparation of β,γ-methano-GABA derivatives.

The Kulinkovich-de Meijere reaction between an unsaturated Grignard reagent and a chiral amide takes place with a high trans stereoselectivity and provides a convenient access to non-racemic trans cyclopropylamines. These compounds are transformed in four steps into the corresponding N-protected β,γ-methano-GABA derivatives, which are obtained for the first time in enantiomerically pure form. The corresponding transformations of the cis cyclopropylamine adducts are also described.

A C-linked glycomimetic in the gas phase and in solution: synthesis and conformation of the disaccharide Manalpha(1,6)-C-ManalphaOPh.

The effect of carbon is subtle but sweet: The flexible C-linkage in the newly synthesised C-glycosyl mimetic, Manalpha(1,6)-C-ManalphaOPh allows OH--pi bonding, both in the gas phase and in aqueous solution. This interaction is absent in the O-linked disaccharide (see figure).The intrinsic conformational preference of a newly synthesised glycomimetic, the C-linked disaccharide Manalpha(1,6)-C-ManalphaOPh (1), has been determined in the gas phase at about 10 K by infrared ion dip spectroscopy coupled with density functional theory and ab initio calculations, and compared with its dynamical conformation in aqueous solution at 298 K by NMR spectroscopy.

Two methods for catalytic generation of reactive enolates promoted by a chiral poly gd complex: application to catalytic enantioselective protonation reactions.

A chiral polynuclear Gd complex derived from Gd(O(i)Pr)(3) and FujiCAPO (2 or 3) catalytically generated Gd enolates through two distinct methods; transmetalation from enol silyl ethers and conjugate addition of cyanide to alpha,beta-unsaturated N-acyl pyrroles. These chiral enolates can be enantioselectively protonated by a proton in an asymmetric environment in the polynuclear catalyst. Thus, catalytic enantioselective protonation of enol silyl ethers was promoted by the Gd catalyst (5-10 mol %) in the presence of a stoichiometric amount of 2,6-dimethylphenol.

4-Methoxy-phenyl 2,3,4,6-tetra-O-acetyl-1-thio-α-d-mannopyran-oside.

The title compound, C(21)H(26)O(10)S, was synthesized in a single step from mannose penta-acetate. The mol-ecular structure confirms the α configuration of the anomeric thioaryl substituent. Spectroscopic and melting-point data obtained for the title compound are in disagreement with those previously reported, indicating the previously reported synthesis [Durette & Shen (1980 ▶).

2,3,4,6-Tetra-O-benzoyl-4-nitro-phenyl-1-thio-α-d-mannopyran-oside-dichloro-methane-diethyl ether mixed solvate (1/0.53/0.38).

The title compound, C(40)H(31)NO(11)S·0.53CH(2)Cl(2)·0.38C(4)H(10)O, was synthesized in two steps from mannose penta-acetate and single crystals were grown by slow evaporation.

At point of use sono-electrochemical generation of hydrogen peroxide for chemical synthesis: the green oxidation of benzonitrile to benzamide.

At point of use generation of synthetically useful quantities of hydrogen peroxide in a non-optimized sono-electrochemical cell is reported. Proof-of-concept of the use of this procedure for green synthesis is given through the oxidation of benzonitrile to benzamide with yields similar to those obtained via bulk chemical synthesis.

Voltammetric and electrochemical ESR studies of oxidation reactions mediated by tris(4-bromophenyl)amine in acetonitrile.

The electrochemical oxidation of tris(4-bromophenyl)amine in the presence of 2,6-lutidine is examined in acetonitrile. Voltammetric and spectroscopic investigations suggest that the electrogenerated triaryl aminium radical cation oxidizes 2,6-lutidine in an EC' mechanism, and an equilibrium constant for this homogeneous electron transfer is estimated. The mediated oxidation of a protected phenyl selenoglycoside by this reaction mixture is studied by the use of electrochemical ESR, employing a tubular flow cell, and signal intensity data is found to be consistent with the proposed mechanism, allowing the determination of kinetic parameters by computational simulation.