吲哚咔唑作为有效的细胞周期蛋白D1-细胞周期蛋白依赖性激酶4抑制剂的合成、构效关系及生物学研究
Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors.
作者信息
Zhu Guoxin, Conner Scott E, Zhou Xun, Shih Chuan, Li Tiechao, Anderson Bryan D, Brooks Harold B, Campbell Robert Morris, Considine Eileen, Dempsey Jack A, Faul Margaret M, Ogg Cathy, Patel Bharvin, Schultz Richard M, Spencer Charles D, Teicher Beverly, Watkins Scott A
机构信息
Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
出版信息
J Med Chem. 2003 May 22;46(11):2027-30. doi: 10.1021/jm0256169.
Novel substituted indolocarbazoles were synthesized, and their kinase inhibitory capability was evaluated in vitro. 6-Substituted indolocarbazoles 4 were found to be potent and selective D1/CDK4 inhibitors. 4d and 4h exhibited potent and ATP-competitive D1/CDK4 activities with IC50 values of 76 and 42 nM, respectively. Both compounds had high selectivity against the other kinases. These D1/CDK4 inhibitors inhibited tumor cell growth, arrested tumor cells at the G1 phase, and inhibited pRb phosphorylation.
合成了新型取代吲哚咔唑，并在体外评估了它们的激酶抑制能力。发现6-取代吲哚咔唑4是有效的选择性D1/CDK4抑制剂。4d和4h表现出有效的ATP竞争性D1/CDK4活性，IC50值分别为76和42 nM。这两种化合物对其他激酶具有高选择性。这些D1/CDK4抑制剂抑制肿瘤细胞生长，使肿瘤细胞停滞在G1期，并抑制pRb磷酸化。
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