Recent studies have shown additive and synergistic effects associated with the combination of kinase inhibitors. BRAF^V600E and EGFR are attractive targets for many diseases treatments and have been studied extensively. In keeping with our interest in developing anticancer targeting EGFR and BRAF^V600E, a novel series of 2,3-dihydropyrazino[1,2-a]indole-1,4-dione has been rationally designed, synthesized and evaluated for their antiproliferative activity against a panel of four human cancer cell lines. Compounds 20–23, 28–31, and 33 showed promising antiproliferative activities. These compounds were further tested for their inhibitory potencies against EGFR and BRAF^V600E kinases with erlotinib as a reference drug. Compounds 23 and 33 exhibited equipotency to doxorubicin against the four cell lines and efficiently inhibited both EGFR (IC₅₀ = 0.08 and 0.09 µM, respectively) and BRAF^V600E (IC₅₀ = 0.1 and 0.29 µM, respectively). In cell cycle study of MCF-7 cell line, compounds 23 and 33 induced apoptosis and exhibited cell cycle arrest in both Pre-G1 and G2/M phases. Molecular docking analyses revealed that the new compounds can fit snugly into the active sites of EGFR, and BRAF^V600E kinases. Compound 23, 31 and 33 adopted similar binding orientations and interactions to those of erlotinib and vemurafenib.

最近的研究表明与激酶抑制剂的组合有关的加和协同作用。BRAF ^V600E和EGFR是许多疾病治疗的诱人靶标，并且已得到广泛研究。为了符合我们对靶向EGFR和BRAF ^V600E的抗癌^药的兴趣，已经合理设计，合成和评估了一系列新型的2,3-二氢吡嗪并[1,2 - a ]吲哚-1,4-二酮，针对它们的抗增殖活性一组四个人类癌细胞系。化合物20 - 23，28 - 31，和33显示出有希望的抗增殖活性。以厄洛替尼为参比药物，进一步测试了这些化合物对EGFR和BRAF ^V600E激酶的抑制作用。化合物23和33对四种细胞系具有阿霉素的等效性，并有效抑制EGFR（IC _50分别 为0.08和0.09 µM）和BRAF ^V600E（IC _50分别 为0.1和0.29 µM）。在MCF-7细胞系的细胞周期研究中，化合物23和33在前G1期和G2 / M期均诱导细胞凋亡并表现出细胞周期停滞。分子对接分析表明，新化合物可以紧贴EGFR和BRAF ^V600E激酶的活性位点。化合物23，31和33通过了类似的结合取向和相互作用的那些厄洛替尼和威罗菲尼的。