Identification and Optimization of New Dual Inhibitors of B-Raf and Epidermal Growth Factor Receptor Kinases for Overcoming Resistance against Vemurafenib
Identification and Optimization of New Dual Inhibitors of B-Raf and Epidermal Growth Factor Receptor Kinases for Overcoming Resistance against Vemurafenib
复制标题
用于克服 Vemurafenib 耐药性的新型 B-Raf 和表皮生长因子受体激酶双重抑制剂的鉴定和优化
DOI：
10.1021/jm500007h
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发表时间：
2014-03-27
影响因子：
7.3
通讯作者：
Ding, Ke
中科院分区：
文献类型：
--
作者：
Cheng, Huimin;Chang, Yu;Ding, Ke
表皮生长因子受体（EGFR）扩增已被证明是黑色素瘤和结直肠癌患者对当前B-Raf（V600 E）抑制剂治疗的固有和/或获得性耐药性的关键。我们报道了一系列1H-吡唑并[3，4-B]吡啶-5-甲酰胺类似物作为EGFR和B-Raf（V600 E）突变体双重抑制剂的发现和构效关系研究。最有前途的化合物之一，6a，有效地抑制这两种ldnases的IC 50值分别为8.0和51 nM。该化合物还以亚微摩尔IC 50值强烈抑制了一组固有和获得性耐药的黑色素瘤和/或结直肠癌细胞的增殖，所述黑色素瘤和/或结直肠癌细胞具有过表达的EGFR。进一步的机制研究表明，6a可持续抑制耐药SK-MEL-28 PR 30黑色素瘤细胞和EGFR扩增的WiDr结直肠癌细胞中MAPK通路的激活。我们的研究结果支持以下假设：EGFR/B-Raf（V600 E）双重抑制可能是克服黑色素瘤和/或结直肠癌对当前B-Raf（V600 E）抑制剂治疗的内在和获得性耐药性的一种易处理的策略。
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 activity 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 ldnases 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.