Guanidinium-like protein kinase inhibitors as anticancer agents

Protein kinases (PKs), which are one of the largest family of human proteins and the second most important group of drug targets, are currently being rigorously researched in medicinal chemistry. The RAS–RAF–MEK–ERK (MAPK) and JAK/STAT signalling cascades are important in gene regulation as well as in promoting cell growth, proliferation and evasion of apoptosis. It has been found that components of these cascades are mutated in several cancers and one of the most commonly mutated kinase in the MAPK signalling cascade is B-RAF and JAK in the JAK/STAT cascade leading to the development of novel inhibitors targeting these pathways.

Previous work in the Rozas’ group identified an allosteric type III inhibitor of the B-RAF kinase. Biochemical studies have also shown that a derivative of this compound did not target the same kinase, rather it was shown to target the JAK/STAT pathway. This project focuses on the computational studies, synthesis and biological evaluation of derivatives as protein kinase inhibitors for the treatment of cancer.