Building molecules for the modulation of age-related diseases

• Main Author: Dwyer, Jessica E.
• Published: University of Sussex 2016
• Subjects: 572; QD0415 Biochemistry
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.698701

Improved understanding of normal human ageing will provide important insights into major risk factors for many age-related diseases. Using the progeroid disease Werner syndrome (WS) as a model for accelerated ageing, this project aimed to investigate how modulation of protein function in the p38α stress-signalling kinase cascade could affect ageing on the cellular level. New rapid routes towards p38α and MK2 inhibitors have been developed to evaluate their use as chemical probes to investigate the mechanisms of cellular ageing. The p38α inhibitor RO3201195 has been synthesized and used as a probe to corroborate previously published evidence that inhibition of the p38α protein kinase reverses the aged morphology of WS fibroblasts. A new route for the synthesis of the MK2 inhibitor PF-3644022 was developed, exploring new methods for building the heterocyclic scaffold through a number of retrosynthetic strategies. Microwave-assisted organic synthesis was used extensively as a tool towards halogenated benzothiophenes and fused quinoline systems, and in rapid Suzuki-Miyaura coupling and Buchwald-Hartwig N-arylation chemistry. This MK2 inhibitor can now be used as a readily accessible probe to further investigate the role of kinases downstream of p38α and the role of MK2 in the premature ageing of WS cells. The final part of the project focussed on the potential of a known p38α inhibitor, BIRB 796, in the development of new chemical probes. BIRB 796 binds allosterically outside of the ATPbinding pocket of p38α MAPK, which drives a conformational change of the kinase into an inactive form. Using rapid synthetic methods towards pyrazole and urea formation, the selectivity elements of the inhibitor were reviewed and a new library of analogues was synthesized. Upon testing against a small panel of kinases, it was found that through small changes the inhibitor potency for p38α could be dramatically altered, and binding affinity for alternative kinases could be selectively enhanced.