The mitogen‐activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated components, especially the kinase B‐Raf^V600E. New inhibitors of the kinase are needed as cases of relapse and resistance with the known drugs have been widely reported in the clinic. In the present work, a new class of B‐Raf^V600E inhibitors was identified by fragment linking. In vitro and in vivo assays were used to demonstrate the pharmacological properties of the compounds. 3‐{3‐[4‐Chloro‐3‐(trifluoromethyl)phenyl]ureido}‐N‐[1‐(4‐methoxyphenyl)‐1H‐pyrazol‐4‐yl]benzamide was the most potent agent with IC₅₀ values of 0.035±0.004 μm (B‐Raf^V600E kinase) and 0.39±0.04 μm (A375 cells). Furthermore, no obvious toxicity was observed. Collectively, the results favored justified the design rationale and hinted that this new chemotype might be worth studying further to develop novel B‐Raf inhibitor candidates.

中文翻译：

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新型II型B-RafV600E抑制剂的鉴定和生物学评估

丝裂原激活的蛋白激酶（MAPK）途径在信号转导网络中起着至关重要的作用。如果被突变的成分（尤其是激酶B-Raf ^V600E）干扰，则可能引发严重疾病。由于在临床上已经广泛报道了复发和已知药物的耐药性，因此需要新的激酶抑制剂。在目前的工作中，通过片段连接鉴定出一类新的B-Raf ^V600E抑制剂。体外和体内测定用于证明化合物的药理特性。3- {3- [4-氯-3-（三氟甲基）苯基]脲基} -N- [1-（4-甲氧基苯基）-1H-吡唑-4-基]苯甲酰胺是最有效的药物，IC ₅₀值的0.035±0.004μ米（B-Raf的^V600E激酶）和0.39±0.04μ米（A375细胞）。此外，未观察到明显的毒性。总的来说，该结果支持合理的设计原理，并暗示这种新的化学型可能值得进一步研究以开发新型的B-Raf抑制剂候选物。