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Al-Ashmawy AA, Ragab FA, Elokely KM, Anwar MM, Perez-Leal O, Rico MC, Gordon J, Bichenkov E, Mateo G, Kassem EM, Hegazy GH, Abou-Gharbia M, Childers W
Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kalpha/mTOR inhibitors
Bioorg Med Chem Lett (2017) 27:3117-3122.
PI3Kalpha/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2-d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kalpha/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC50 values ranging from single to double digit nM. Unlike many PI3Kalpha/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kalpha. Based on its potent enzyme inhibitory activity, selectivity for PI3Kalpha and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC50 against MCF7 breast cancer cells as well as for docking studies with both enzymes.
Publication Date: 2017-07-15.
Last updated on Thursday, May 02, 2019