- Potent and selective inhibitors of glutathione S-transferase omega 1 that impair cancer drug resistance
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Glutathione S-transferases (GSTs) are a superfamily of enzymes that conjugate glutathione to a wide variety of both exogenous and endogenous compounds for biotransformation and/or removal. Glutathione S-tranferase omega 1 (GSTO1) is highly expressed in human cancer cells, where it has been suggested to play a role in detoxification of chemotherapeutic agents. Selective inhibitors of GSTO1 are, however, required to test the role that this enzyme plays in cancer and other (patho)physiological processes. With this goal in mind, we performed a fluorescence polarization activity-based protein profiling (fluopol-ABPP) high-throughput screen (HTS) with GSTO1 and the Molecular Libraries Small Molecule Repository (MLSMR) 300K+ compound library. This screen identified a class of selective and irreversible α-chloroacetamide inhibitors of GSTO1, which were optimized to generate an agent KT53 that inactivates GSTO1 with excellent in vitro (IC50 = 21 nM) and in situ (IC50 = 35 nM) potency. Cancer cells treated with KT53 show heightened sensitivity to the cytotoxic effects of cisplatin, supporting a role for GSTO1 in chemotherapy resistance.
- Tsuboi, Katsunori,Bachovchin, Daniel A.,Speers, Anna E.,Spicer, Timothy P.,Fernandez-Vega, Virneliz,Hodder, Peter,Rosen, Hugh,Cravatt, Benjamin F.
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supporting information; experimental part
p. 16605 - 16616
(2011/12/04)
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- Selective small molecules blocking HIV-1 tat and coactivator PCAF association
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Development of drug resistance from mutations in the targeted viral proteins leads to continuation of viral production by chronically infected cells, contributing to HIV-mediated immune dysfunction. Targeting a host cell protein essential for viral reproduction, rather than a viral protein, may minimize the viral drug resistance problem as observed with HIV protease inhibitors. We report here the development of a novel class of N1-aryl-propane-1,3-diamine compounds using a structure-based approach that selectively inhibit the activity of the bromodomain of the human transcriptional co-activator PCAF, of which association with the HIV trans-activator Tat is essential for transcription and replication of the integrated HIV provirus. Copyright
- Zeng, Lei,Li, Jiaming,Muller, Michaela,Yan, Sherry,Mujtaba, Shiraz,Pan, Chongfeng,Wang, Zhiyong,Zhou, Ming-Ming
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p. 2376 - 2377
(2007/10/03)
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- Design and synthesis of new ethylenediamine or propylenediamine diacetic acid derivatives for Re(I) organometallic chemistry
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A general synthetic approach for a novel range of bifunctional chelating agent (BCA) for the 'fac-[M(CO)3]+' core (M= 99mTc, 99Tc or Re) has been developed. The strategy includes the facile preparation of these tridentate ligands possessing a tertiary amine bearing two carboxylic acid functions as coordinating site and an aromatic amino group for coupling to a biovector. First complexation study has shown that these compounds act exclusively as tridentate ligands (via the two acids and the tertiary amine functions). The convenient synthesis of these new ligands coupled with their high affinity for Re(I) make them quite promising for biomedical applications.
- Allali, Mustapha,Benoist, Eric,Habbadi, Nouzha,Gressier, Marie,Souizi, Abdelaziz,Dartiguenave, Michèle
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p. 1167 - 1174
(2007/10/03)
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