Gaston Stanislas Marcella Diels

The Role of the Alcohol and Carboxylic Acid in Directed Ruthenium-Catalyzed C(sp3)H α-Alkylation of Cyclic Amines

A general directed Ru-catalyzed C(sp(3))-H α-alkylation protocol for piperidines (less-reactive substrates than the corresponding five-membered cyclic amines) has been developed. The use of a hindered alcohol (2,4-dimethyl-3-pentanol) as the solvent and catalyst activator, and a catalytic amount of trans-1,2-cyclohexanedicarboxylic acid is necessary to achieve a high conversion to product. This protocol was used to effectively synthesize a number of 2-hexyl- and 2,6-dihexyl piperidines, as well as the alkaloid (±)-solenopsin A. Kinetic studies have revealed that the carboxylic acid additive has a significant effect on catalyst initiation, catalyst longevity, and reverses the reaction selectivity compared with the acid-free reaction (promotes alkylation versus competing alkene reduction).

Synthesis and biological evaluation of imidazol-2-one and 2-cyanoiminoimidazole derivatives: novel series of PDE4 inhibitors

This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.

Abstract 3229: Managing stress: Discovery of inhibitors of the atypical kinase eEF2K and the class III PI3K, VPS34

Adaptation to nutrient deprivation in the tumour microenvironment was recently shown to be dependent on the appropriate regulation of protein elongation rate through activation of the atypical kinase, eukaryotic elongation factor 2 kinase (eEF2K) (Leprivier et al., 2013, Cell 153(5):1064-79). We have solved the crystal structure of the kinase domain of eEF2K, and used structure-based design as well as screening approaches to optimize a chemical series into single-digit nM inhibitors of eEF2K, with remarkable selectivity across the protein kinome (only 5-10 kinases out of 400 tested are inhibited to more than 50% at 1 μM). These compounds inhibit the phosphorylation of eEF2 in nutrient-starved or metabolically stressed cells, and increase protein elongation rates through stabilization of the ribosomal elongation complex under stress. Evotec9s Cellular Target Profiling of these compounds in cell lysates, revealed that a subset of the eEF2K inhibitors also bind with low nM affinity to the class III phosphatidylinositol-3-kinase, VPS34, but not to class I or II PI3Ks, and pull down the entire beclin-UVRAG-VPS34 complex. Proteomic and biochemical screening of the compound set enabled deconvolution of potent EF2K versus VPS34 inhibitors. Inhibition of VPS34 results in abrogation of autophagic flux, as indicated by rapid and massive accumulation of p62, and impairs survival in specific subsets of tumor cell lines, consistent with a pro-survival role for autophagy in those models (Cheng et al., 2013, Pharmacol Rev 65(4):1162-97). Interestingly, a whole-genome pooled shRNA screen in a KRAS/PI3KCA mutant colorectal cancer cell line revealed that reduction of beclin levels significantly increased sensitivity to VPS34 inhibition. In contrast, inhibition of eEF2K does not appear to be anti-proliferative across a wide panel of cancer cell lines under standard cell culture conditions. Our work has provided the first potent inhibitors to unravel the functional relevance of eEF2K and VPS34 in adaptation to cellular stress, and to examine the utility of inhibiting these kinases in nutrient-deprived and/or autophagy-addicted tumours. Citation Format: Matthias Versele, Claire Moore, Christopher G. Proud, Cindy Rockx, Inez Van de Weyer, Kurt Van Baelen, Stephanie Blencke, Sebastian K. Wanndinger, Gaston Diels, Didier Berthelot, Marcel Viellevoye, Bruno Schoentjes, Berthold Wroblowski, Lieven Meerpoel, William N. Hait. Managing stress: Discovery of inhibitors of the atypical kinase eEF2K and the class III PI3K, VPS34. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3229. doi:10.1158/1538-7445.AM2014-3229