Identification and Optimization of New Dual Inhibitors of B-Raf and Epidermal Growth Factor Receptor Kinases for Overcoming Resistance against Vemurafenib

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• 作者：Huimin Cheng ; Yu Chang ; Lianwen Zhang ; Jinfeng Luo ; Zhengchao Tu ; Xiaoyun Lu ; Qingwen Zhang ; Jibu Lu ; Xiaomei Ren ; Ke Ding
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2692-2703
• 全文大小：517K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

Epidermal growth factor receptor (EGFR) amplification has been demonstrated to be critical for the inherent and/or acquired resistance against current B-Raf^V600E inhibitor therapy for melanoma and colorectal cancer patients. We describe the discovery and structure鈥揳ctivity relationship study of a series of 1H-pyrazolo[3,4-b]pyridine-5-carboxamide analogues as novel dual inhibitors of EGFR and B-Raf^V600E mutant. One of the most promising compounds, 6a, potently inhibited both of the kinases with IC₅₀ values of 8.0 and 51 nM, respectively. The compound also strongly suppressed the proliferation of a panel of intrinsic and acquired resistant melanoma and/or colorectal cancer cells harboring overexpressed EGFR with submicromolar IC₅₀ values. Further mechanism investigation revealed that 6a could sustainably inhibit the activation of the MAPK path way in the resistant SK-MEL-28 PR30 melanoma cancer cells and WiDr colorectal cancer cells with EGFR amplification. Our results support the hypothesis that the EGFR/B-Raf^V600E dual inhibition might be a tractable strategy to overcome the intrinsic and acquired resistance of melanoma and/or colorectal cancers against the current B-Raf^V600E inhibitor therapy.