Implementatie van Carboxylaatisosteren met als doel Remmers van Inflammatoire Caspasen te Optimaliseren

Datum: 4 september 2017

Locatie: UAntwerpen - Campus Drie Eiken - Gebouw Q - Promotiezaal - Universiteitsplein 1 - 2610 Antwerpen (Wilrijk) (route: UAntwerpen, Campus Drie Eiken)

Tijdstip: 16 - 18 uur

Promovendus: Yves Adriaenssens

Promotor: Pieter Van der Veken

Co-promotor: Koen Augustyns

Korte beschrijving: Doctoraatsverdediging Yves Adriaenssens - Faculteit Farmaceutische, Biomedische en Diergeneeskundige Wetenschappen


Dysregulated caspase-1 is involved in the pathogenesis of inflammatory conditions such as atherosclerosis, type-2 diabetes, gout and rare autoinflammatory disorders. The enzyme is therefore considered an excellent target for influencing these pathological processes via inhibitor-mediated blocking of protease activity. Since selective inhibition of one member of the caspase family remains a major obstacle in drug discovery, only two inhibitors of caspase-1 have found their way into clinical trials. The lack of selectivity for individual caspases is mainly due to the overlapping substrate specificity among caspases. In general, caspases have a strong preference for aspartic acid in the S1 binding site, leading to the presence of carboxylic acids in nearly all known peptide and non-peptide caspase inhibitors. Consequently, enhancing selectivity could be achieved by modifying the side group of the preferred aspartic acid residue. The application of bioisosteres has been adopted as a fundamental tactical approach to overcome a number of handicaps associated with design and development of drug candidates. Yet, limited cases of carboxylic acid isosteres have been reported for caspase inhibitor discovery.

The investigation of this PhD was set up to identify isosteric replacements of carboxylates with respect to inhibitor discovery for inflammatory caspases-1 and -4. This was achieved by performing the Modified Substrate Activity Screening (MSAS), a methodology that was recently devised by our group and has so far been validated in inhibitor discovery for urokinase plasminogen activator (uPA) and Atg4B. Two isosteres were identified; acylsulfonamides and oxadiazolones. Both functional groups were implemented in existing caspase inhibitors by replacing the original carboxylate moiety. The influence on affinity and selectivity towards a panel of caspases will be presented, along with in vitro physicochemical and pharmacokinetic properties. Moreover, the acylsulfonamide subgroup was subject of a thorough NMR study, leading to mechanistic insights on the limited stability of acylsulfonamides combined with aldehyde warheads. This allowed for the design and synthesis of analogues with optimized in vitro pharmacokinetic characteristics.

Furthermore, an exploratory study was performed towards easy library synthesis using the acyliminium-Strecker reaction, in order to produce large sets of aminonitriles in a time-efficient way. The latter is considered highly suitable for caspase drug design because of the production of biocompatible molecules and their direct implementation of a warhead functionality. A promising one-pot protocol was devised with consecutive amidosulfone production and a quinine-catalyzed Strecker synthesis to afford aminonitriles.