Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan Kyeonggi-do 426-791, Republic of Korea.
Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan Kyeonggi-do 426-791, Republic of Korea.
Bioorg Med Chem Lett. 2019 Feb 15;29(4):534-538. doi: 10.1016/j.bmcl.2019.01.003. Epub 2019 Jan 4.
Notorious oncogenic BRAF V600E plays a significant role in the signal transduction of the MAPK pathway, which is involved in tumor growth, especially in melanoma. Much effort has been made to suppress BRAF V600E through small molecules like vemurafenib and dabrafenib, but the MAPK pathway remains active through paradoxical activation, where CRAF transmits the signal of the MAPK pathway either alone or along with BRAF V600E. Therefore, we designed and synthesized a new series of N-(3-(3-alkyl-1H-pyrazol-5-yl) phenyl)-aryl amide/urea analogues that showed potent inhibitory activities against BRAF V600E and CRAF. Compound 7c exhibited particularly superior selectivity toward BRAF V600E and CRAF over 30 other protein kinases, implying that this chemotype could be investigated as a BRAF paradox breaker. © 2019 Elsevier Ltd. All rights reserved.
致癌 BRAF V600E 在 MAPK 通路的信号转导中起着重要作用，该通路参与肿瘤生长，尤其是黑色素瘤。已经做了大量努力通过小分子如 vemurafenib 和 dabrafenib 来抑制 BRAF V600E，但 MAPK 通路仍然通过反常激活保持活性，其中 CRAF 单独或与 BRAF V600E 一起传递 MAPK 通路的信号。因此，我们设计并合成了一系列新型的 N-(3-(3-烷基-1H-吡唑-5-基)苯基)-芳基酰胺/脲类似物，它们对 BRAF V600E 和 CRAF 表现出很强的抑制活性。化合物 7c 对 BRAF V600E 和 CRAF 的选择性明显优于其他 30 多种蛋白激酶，这表明这种化学型可以作为 BRAF 反常激活抑制剂进行研究。© 2019 爱思唯尔有限公司。保留所有权利。
