The mitogen-activated protein kinase pathway (MAPK) is a three-tiered signal transduction pathway which involves sequential phosphorylation of interrelated serine/threonine and tyrosine protein kinases. In this pathway, the mitogen-activated protein kinase kinase (MAP2K or MEK) phosphorylates and activates an extracellular signal-regulated kinase (ERK) which in turn activates transcriptional factors to mediate important cellular functions like growth, division, and differentiation. Out of seven isoforms of MEK, MEK1 and 2 are extensively studied. However, increased expression of the less studied MEK5/ERK5 pathway is reported in various types of cancers, especially in triple negative breast cancer (TNBC). It was regarded as useful to develop selective MEK5 inhibitors as a pharmacological tool to understand the role of MEK5 in various biological processes relevant to TNBC. The quinazoline core has been suggested to bind to the hinge region of the ATP site of MEK5. In-silico docking studies, with a homology model of MEK5, permitted rational design of quinazoline derivatives as selective MEK5 inhibitors. Various aryl/alkyl substitutions at the C-6 of the quinazoline core have been synthesized using Suzuki/modified Suzuki reactions. A variety of amine derivatives have been substituted at C-4 of the quinazoline core. These derivatives were tested in breast cancer cell lines using western blot analysis. Inhibition of MEK5 and selectivity against MEK1/2 was evaluated by quantitation of pERK5 and pERK1/2. Our efforts resulted in the identification of promising leads for further optimization.

4,6-Disubstituted quinazoline derivatives as inhibitors of the MEK5/ERK5 pathway

256th National Meeting (2018)

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