Potent and selective farnesyl transferase inhibitors.
Potent and selective farnesyl transferase inhibitors.
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有效且选择性的法尼基转移酶抑制剂。
DOI：
10.1021/jm030502y
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发表时间：
2004
影响因子：
7.3
通讯作者：
J. Hénichart
中科院分区：
文献类型：
--
作者：
R. Millet;J. Domarkas;R. Houssin;P. Gilleron;J. Goossens;P. Chavatte;C. Logé;N. Pommery;J. Pommery;J. Hénichart
我们最近描述了一系列新的CA(1)A(2)X多肽类化合物作为法尼基转移酶抑制剂(FTI)。这些化合物具有模拟A(1)A(2)残基的N-(4-哌啶基)苯甲酰胺支架。广泛的构效关系研究表明，半胱氨酸被取代的苯并咪唑提供了具有体外活性的纳米分子FTI(18E，IC(50)=4.60 nM，对肿瘤细胞系的生长抑制EC(50)=20.0 nM)。18E和19E在酶活性部位的分子对接提供了与蛋白质关键相互作用的细节，并表明蛋氨酸或苯丙氨酸残基适合芳基结合部位。
We recently described a novel series of CA(1)A(2)X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A(1)A(2) residue. Extensive exploration of structure--activity relationships revealed that replacement of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro activities (18e, IC(50) = 4.60 nM on isolated enzyme, EC(50) = 20.0 nM for growth inhibition on a tumor cell line). The molecular docking of 18e and 19e in the active site of the enzyme provided details of key interactions with the protein and showed that the methionine or phenylalanine residue fits into the aryl binding site.