Synthesis and Preliminary Biological Evaluation of Novel Inhibitors of Deubiquitinating Enzymes

Abstract

Virtually every process within eukaryotic cells is regulated by the post translational modification of proteins with the marker protein, ubiquitin. The covalent addition of ubiquitin to a target protein is a reversible process, known as deubiquitination and is catalysed by deubiquitinating enzymes (DUBs). WP1130 is a deubiquitinating enzyme (DUB) inhibitor found to mediate ubiquitination of the tyrosine kinase, Janus Kinase (JAK2), supressing its activity in the JAK2-STAT3 cell signalling pathway; constitutive activation of this pathway has been frequently detected in cancer. The synthesis of small drug molecules with inhibitory effects on these cell signalling mediators, capable of inactivating tumour growth-promoting signalling pathways, are of interest, proving to be effective cancer therapeutics. On-going research being carried out in the Whitehead group has demonstrated successful synthesis of alkyne-containing analogues of WP1066, which have undergone biological testing. Building on from this, the development of WP1130 analogues possessing an acetylene moiety, which could be utilised in click chemistry, was proposed. The functionalisation would aid in the attachment of an ER-directing molecular fluorescent probe, allowing sub-cellular targeting and visualisation under fluorescent microscopy. Upon successful synthesis, alkyne analogues of WP1130 were to undergo biological evaluation in order to explore their DUB inhibitory profile, in comparison to the parent compound WP1130. This investigation aimed to expand the Whitehead group’s current research into the bioactivity of the WP compounds.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Eileithyia Swanton (Supervisor) & Roger Whitehead (Supervisor)