Development of Heterocyclic Scaffolds as Inhibitors of Splicing Kinases

摘要

This thesis is focused on the development of synthetic pathways to heterocyclic scaffolds that show inhibitory activity on splicing kinases, and onthe investigation of structure-activity relationships of these scaffolds.In Chapter 1, the significance of kinases as therapeutic targets was described, with an emphasis on splicing kinases. Previous work in the groupwas discussed and revealed that a new scaffold based on the 5-(2-aminopyrimidinyl)pyrrolo[1,2-c]pyrimidine ring system could have greatpotential for the development of CLKs and DYRKs inhibitors.Chapter 2 investigates the effect of different aromatic substituents at the 5 position of the pyrrolo[1,2-c]pyrimidine scaffold on the inhibitory activity.In order to do so, a new methodology to access to the pyrrolo[1,2-c]pyrimidine core was developed. Further optimization of the synthesis allowedthe generation of a library of compounds. A sample of the library was tested on a panel of kinases, including the DYRKs and CLKs. However,these compounds did not exhibit significant activity against the splicing kinases, which leads to the conclusion that the pendant ring must beheterocyclic if these kinases are to be targeted.In Chapter 3 the effect of heteroatoms on the pendant ring at the 5 position of the scaffold was examined. The 5-(2-aminopyrimidinyl)pyrrolo[1,2-c]pyrimidine analog library was expanded and two new compounds bearing different heteroaromatic pendant rings were generated. DSF assaysrevealed that two compounds generated were potent inhibitors for CLKs and DYRKs, with 3.10 having excellent prospects as a chemical probe.This data, together with the crystal structures of two of the analogs co-crystallised with CLK1, allowed the rationalisation of the structure-activityrelationships of these compounds.In Chapter 4, efforts were focused on developing a pathway to a recently reported inhibitor of PRP4 kinase, Compound A. Structural variations onthe scaffold were proposed in order to improve the compound’s drug-like properties. The synthetic approaches undertaken in order to accessthese compounds were described, with a pathway to access analogs successfully developed.A summary of the work described in this thesis and the future directions for the project are given in Chapter 5, while full experimental procedureshave been provided in Chapter 6.