Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors.
Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors.
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DOI：
10.1021/jm400221d
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发表时间：
2013-05-23
影响因子：
7.3
通讯作者：
Sebti, Said M.
中科院分区：
文献类型：
--
作者：
Ozcan, Sevil;Kazi, Aslamuzzaman;Marsilio, Frank;Fang, Bin;Guida, Wayne C.;Koomen, John;Lawrence, Harshani R.;Sebti, Said M.
Screening of the 50,000 ChemBridge compound library led to the identification of the oxadiazole-isopropylamide 1 (PI-1833) which inhibited CT-L activity (IC50 0.60 μM) with little effects on the other 2 major proteasome proteolytic activities, T-L and PGPH-L. LC/MS-MS and dialysis show that 1 is a non-covalent and rapidly reversible CT-L inhibitor. Focused library synthesis provided 11ad (PI-1840) with CT-L activity (IC50 27 nM). Detailed SAR studies indicate that the amide moiety and the 2 phenyl rings are sensitive toward modifications. Hydrophobic residues, such as propyl or butyl, in the para-position (not ortho or meta) of the A-ring and a meta-pyridyl group as B-ring significantly improve activity. Compound 11ad (IC50 0.37 μM) is more potent than 1 (IC50 3.5 μM) at inhibiting CT-L activity in intact MDA-MB-468 human breast cancer cells and inhibiting their survival. The activity of 11ad warrants further pre-clinical investigation of this class as non-covalent proteasome inhibitors.
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