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  • (2018) Hawtrey, Tom
    This thesis describes the development of small molecules inhibitors of the CLK, DYRK and SRPK splicing kinases. Chapter 1 outlines the importance of alternative splicing in controlling cellular function and highlights the value of small molecule inhibitors of the splicing kinases as chemical probes or therapeutic agents. Prior work in the Morris group on the development of novel inhibitors was summarised and set the stage for the work to be done. Chapter 2 describes the development of the pyrrolo[1,2-c]pyrimidine scaffold which has previously been shown to inhibit the CLK and DYRK kinases. In this work, synthetic access to this scaffold was optimised, with the two lead compounds synthesised in improved yields of 18% over 9 and 7 steps respectively. This enabled 17 new analogues which varied the C2’, C5 and C1 positions to be prepared. Key analogues were highly potent, with benzylamine 2.36 a 5 nM inhibitor and pyrimidine 2.60 an 8 nM inhibitor of CLK1, both with modest selectivity over DYRK1A. N,N-Dimethylaminoethylamine 2.23 showed enhanced 10-fold selectivity for CLK1 over DYRK1A. Crystal structures revealed that the C2’ substituent occupies an additional portion of the binding site, with these new interactions contributing to the ability to modulate the potency and selectivity. Chapters 3 and 4 detail the investigation of a phenylcarboxamide scaffold, previously shown to inhibit SRPK1. An efficient and divergent synthetic route that allowed the preparation of analogues containing variations at several key substituents in 4-5 steps and good yields was developed. Varying the head group enabled the potent and selective inhibition the CLK kinases, with N-methylpyrazole 3.6 a 6 nM inhibitor of CLK1 with >30-fold selectivity over both DYRK1A and SRPK1. Varying the saturated heterocycle revealed that 2-furanylmethylpiperazino analogues show improved potency but decreased selectivity, while N,N-dimethylaminoethylpiperazino analogues showed improved selectivity for CLK. Varying the carboxylate side chain led to quinoline 3.49 being identified as a highly potent but non-selective DYRK1A inhibitor (IC50=14 nM). X-ray crystallography revealed the importance of these groups for controlling selectivity. The conclusions and future directions of the work are given in Chapter 5 and full experimental procedures have been provided in Chapter 6.