This thesis describes our efforts to design and synthesize selective probes for the PIM kinases (PIM-1, PIM-2, and PIM-3), because of their important role in cancer. During the course of the investigation we also examined the splicing kinases CLK1, CLK3, CLK4, DYRK1, DYRK2, SRPK1, and SRPK2. In Chapter 2, SAR and molecular modelling studies were carried out using a known benzothienopyrimidinone PIM inhibitor1 (J. Med. Chem., 2009, 52, 6621-6636). A series of analogues were synthesized providing low nanomolar activities towards the PIM kinases but showing little selectivity between the isoforms. Within these studies on PIM selectivity, the discovery of potential CLK4 chemical probes was made, which led to the first CLK4 X-ray crystal structure with a compound bound within the ATP binding site. Chapter 3 describes the discovery of a new series of compounds containing a phenyl pyrimidinone core which showed excellent activity against the PIM kinases. The scaffold offered potential for multiple points of diversity and applications in future programmes. A one-pot strategy for the synthesis of the phenyl pyrimidinone core is also described. Chapter 4 presents the discovery of a benzothienodiazepine scaffold. Through SAR studies, molecular modeling, and biological evaluation, potential PIM-1 and PIM-3 selective probes with good selectivity as well as low nanomolar activities are discussed. An X-ray crystal structure of PIM-1 with one of our analogues is also described, confirming that the compound is bound in the PIM-1 ATP binding pocket. Chapter 5 describes the biological evaluation carried out with the potential PIM-1 and PIM-3 selective probes. Solubility, permeability, in vitro and in vivo assays are detailed, providing low nanomolar activities as well as excellent selectivity towards a wide panel of kinases. Selected probes are further being characterized. On validation, our aim is to make these probes available to the biological community in order to dissect the fundamental biology of these important receptors.
|Date of Award||7 Jun 2016|
- University Of Strathclyde
|Sponsors||University of Strathclyde|
|Supervisor||Nick Tomkinson (Supervisor) & Simon MacKay (Supervisor)|