Inhibition of the DHHC superfamily : development of chemical tools

Student thesis: Doctoral Thesis

Abstract

Acylation, the attachment of fatty acids onto cysteine residues, is a major post-translational modification of cellular proteins, catalysed by the DHHC superfamily. The actions of acylation impact on a number of important physiological processes, and defects in these processes have been linked to a range of diseases and disorders. A major effort has been invested in identifying the substrates that DHHC enzymes are active against, however, there is still a lack of understanding of the specific substrate profiles of individual enzymes and how DHHC-substrate specificity is achieved. To begin to assess the downstream effects of palmitoylation by this enzyme superfamily, and in turn assess the possibility of targeting palmitoylation and interrogating its therapeutic potential, chemical tools are required. The University of Strathclyde has established a partnership with Ono Pharmaceuticals, in Japan, and Professor Luke Chamberlain from the Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS). The overall objective from this partnership is to provide chemical probes to elucidate DHHC fatty acid selectivity and DHHC-substrate specificity profiles, and to prepare selective inhibitors for members of the DHHC superfamily. The first short-term aim of the project was to establish selectivity between two DHHC enzymes, DHHC3 and DHHC7, and to develop selective inhibitors of S-acylation. In order to bring this project forward, six series of compounds have been synthesised, and tested within a cell-based assay. Two ‘hit’ compounds have been identified as ‘semi-pan’ inhibitors of S-acylation by the DHHC superfamily.The second part of the project was to develop a tool compound capable of elucidating DHHC-substrate profiles. One such compound was proposed and synthetic routes towards it are under development. The final aim of the project was to provide inhibitors of DHHC2. Three series of compounds have been targeted, synthesised and tested within an in vitro assay. One hit compound has been identified as a potential cysteine selective warhead and an SAR has been carried out.
Date of Award26 Sep 2019
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorNick Tomkinson (Supervisor) & Luke Chamberlain (Supervisor)

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