a Department of Pharmacy and Institute of Pharmaceutical Science and Technology , College of Pharmacy, Hanyang University , Ansan , Gyunggido, Republic of Korea.
b Kohat University of Science and Technology , Kohat , Khyber Pukhtunkhwa , Pakistan.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):1314-1320. doi: 10.1080/14756366.2019.1599366.
BRAF belongs to the upstream portion of the MAPK pathway, which is involved in cell proliferation and survival. When mutations occur in BRAF, downstream MEK and ERK are phosphorylated irrespective of RAS, resulting in melanoma-like cancer. Over the years, small molecules targeting BRAFV600E have been discovered to be very effective melanoma drugs, but they are known to cause the BRAF paradox. Recently, it was shown that this paradox is caused by the heterodimer phenomenon of BRAF/CRAF. Here, we suggest one method by which paradoxical activation can be avoided by selectively inhibiting BRAFV600E and CRAF but not wild-type BRAF. From previous report of -(3-(3-alkyl-1-pyrazol-5-yl) phenyl) aryl amide as a selective inhibitor of BRAFV600E and CRAF, we present compounds that offer enhanced selectivity and efficacy with the aid of molecular modelling.
BRAF 属于 MAPK 通路的上游部分，参与细胞增殖和存活。当 BRAF 发生突变时，下游的 MEK 和 ERK 被磷酸化而不依赖于 RAS，导致类似于黑色素瘤的癌症。多年来，靶向 BRAFV600E 的小分子已被发现是非常有效的黑色素瘤药物，但它们被认为会引起 BRAF 悖论。最近表明，这种悖论是由 BRAF/CRAF 的异二聚体现象引起的。在这里，我们提出了一种方法，通过选择性抑制 BRAFV600E 和 CRAF 而不是野生型 BRAF 来避免悖论性激活。根据先前关于 -(3-(3-烷基-1-吡唑-5-基)苯基)芳基酰胺作为 BRAFV600E 和 CRAF 选择性抑制剂的报道，我们借助分子建模提出了具有增强选择性和疗效的化合物。
