الفهرس 
Cancer as a World ThreatOnly 14 pages are availabe for public view
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Abstract
MAPK pathway sparkles with RTK activation, passes through subsequent downstream RAS-RAF-MEK-ERK signaling cascades, with consequent direct and indirect CDK4/6 signaling activation, and end end end s with cell survival, division, and proliferation. However, the emergence of anomalies in this pathway such as mutations or overexpression in one or more points of the pathway could lead to cancer development and drug resistance. Therefore, designing small-molecule inhibitors to strike multitudinous MAPK pathway steps could be a promising synergistic strategy to confine cancer.<In this study, twelve 6indolylpyridone‐3‐carbonitrile candidates were synthesized as the first series, assessed in vitro for antineoplastic activity on the NCI-60 panel, and followed by target identification of the most promising candidate 3h. later, a second and a third series were designed applying lead optimization strategies via replacement of indolyl moiety with more lipophilic naphthyl moiety (the second series), and then subsequently substitution of the main central pyridin-2(1H)-one by 2-aminopyridine (the third series). The initial antiproliferative screening revealed that the second series (GI% Avg = 44.9%) exhibited superlative anticancer potency compared to the first and third series (GI% Avg = 26.8% and 9.3%, respectively). from the second series, compounds 5b and 5d were the most potent candidates (GI% Avg = 70.4%, and 76.3%, respectively). The subsequent safety and selectivity assessment showed that 5d exhibited 14- and 13- times selectivity toward cancerous CNS and melanoma cells over normal CNS and skin cells, being safer than erlotinib which has SI of 2.51 and 2.41 on CNS and skin, respectively.