Receptor kinases have an important role in several cellular functions including cell division, cell communication, and regulation of signaling pathways. Though several mechanisms have been elucidated for receptor kinases in cellular processes, their roles and exact mechanism in the initiation and progression of uncontrolled cell division are not yet clear. Thus, drug design and development efforts are greatly focused on protein kinases to provide a more in depth knowledge about them as one of the most successful targets for the treatment of different diseases and particularly in cancer. However, development of highly selective inhibitors is still one of the major challenges in medicinal chemistry. Unfortunately, implementations of all rational design strategies into selective and potent binders do not always lead to predict the desired biological effects in vitro and/or in vivo. Here in this project, we have designed and synthesized a series of alkyne-containing pyrazolo [3,4-d] pyrimidine analogues. Furthermore, the effect of these analogues on downstream signals were evaluated in vitro and in vivo. The result showed that desired compounds improved potency and selectivity for inhibition of Braf which is important in cell growth and proliferation. Additionally, selectivity of the optimized molecules compared to the reference compound was evaluated by kinome profiling analysis. Finally, co-crystal of one compound has been prepared that demonstrated the interaction of compound in the active site of protein. The result of this research introduces a novel approach for improving the selectivity of cancer chemotherapy.

Structure-based design to improve the selectivity of kinase inhibitors in cancer therapy

256th National Meeting (2018)

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