Discovery of novel hydroxamates as highly potent tumor necrosis factor-α converting enzyme inhibitors. Part II: Optimization of the S3′ pocket

Mazzola, Robert; Zhu, Zhiwei; Sinning, Lisa; McKittrick, Brian A.; Lavey, Brian J.; Spitler, James; Kozlowski, Joseph A.; Shih, Neng‐Yang; Zhou, Guowei; Guo, Zhuyan; Orth, Peter; Madison, Vincent; Sun, Jing; Lundell, Daniel; Niu, Xiaoda

doi:10.1016/j.bmcl.2008.09.045

Cited by 30 publications

(33 citation statements)

References 24 publications

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“…To address this question, we analyzed shedding from wild-type cells treated with a highly selective inhibitor of ADAM17. When wt mEFs expressing TGF-␣ or L-Selectin were stimulated with PMA or IM, we found complete inhibition of the PMA-and IMstimulated shedding by the highly ADAM17-selective inhibitor SP26 (Mazzola et al, 2008), whereas the ADAM10-selective GI had no detectable effect (Figure 7, A-D, see Supplemental Figure 2 for controls regarding the selectivity of these inhibitors toward ADAM10 and -17). Identical experiments performed with BTC confirmed that GI completely blocked IM-stimulated shedding of this ADAM10 substrate, whereas SP26 did not ( Figure 7E).…”

Section: Selective Inhibitors For Adam17 Demonstrate That the Abilitymentioning

confidence: 92%

“…The hydroxamate inhibitor GI254023X (GI; 10-fold selective for ADAM10 over ADAM17; Hundhausen et al, 2003;Weskamp et al, 2006) was from David Becherer (GlaxoSmithKline, Research Triangle Park, NC), and marimastat was from Ouathek Ouerfelli (Sloan-Kettering Institute, New York, NY). The ADAM17-selective inhibitor SP26 (Mazzola et al, 2008) was from Schering Plough (Kenilworth, NJ). Anti-Phospho-extracellular signal-regulated kinase (ERK) were from Cell Signaling Technology (Beverly, MA), anti-ERK2 antibodies were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA), and anti-human CD23 (30X) was described previously (Weskamp et al, 2006).…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

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ADAMs 10 and 17 Represent Differentially Regulated Components of a General Shedding Machinery for Membrane Proteins Such as Transforming Growth Factor α, L-Selectin, and Tumor Necrosis Factor α

Gall

Bobé

Reiß

et al. 2009

MBoC

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228

313

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Protein ectodomain shedding is a critical regulator of many membrane proteins, including epidermal growth factor receptor-ligands and tumor necrosis factor (TNF)-␣, providing a strong incentive to define the responsible sheddases. Previous studies identified ADAM17 as principal sheddase for transforming growth factor (TGF)-␣ and heparin-binding epidermal growth factor, but Ca ؉؉ influx activated an additional sheddase for these epidermal growth factor receptor ligands in Adam17؊/؊ cells. Here, we show that Ca ؉؉ influx and stimulation of the P2X7R signaling pathway activate ADAM10 as sheddase of many ADAM17 substrates in Adam17؊/؊ fibroblasts and primary B cells. Importantly, although ADAM10 can shed all substrates of ADAM17 tested here in Adam17؊/؊ cells, acute treatment of wild-type cells with a highly selective ADAM17 inhibitor (SP26) showed that ADAM17 is nevertheless the principal sheddase when both ADAMs 10 and 17 are present. However, chronic treatment of wild-type cells with SP26 promoted processing of ADAM17 substrates by ADAM10, thus generating conditions such as in Adam17؊/؊ cells. These results have general implications for understanding the substrate selectivity of two major cellular sheddases, ADAMs 10 and 17.

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Section: Selective Inhibitors For Adam17 Demonstrate That the Abilitymentioning

confidence: 92%

Section: Cell Lines and Reagentsmentioning

confidence: 99%

ADAMs 10 and 17 Represent Differentially Regulated Components of a General Shedding Machinery for Membrane Proteins Such as Transforming Growth Factor α, L-Selectin, and Tumor Necrosis Factor α

Gall

Bobé

Reiß

et al. 2009

MBoC

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228

313

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“…Despite this observation, the complex was successfully crystallized, allowing a 2.1 Å resolution structure to be determined by X-ray crystallography. The overall fold of the ADAM-8 protein resembles the / structure of other MPs (Grams et al, 1995;Botos et al, 1996;Orth et al, 2004;García-Castellanos et al, 2007;Gerhardt et al, 2007;Takeda et al, 2007;Mazzola et al, 2008;Mosyak et al, 2008), with a characteristic central five-stranded -sheet (Fig. 2a) formed by four -strands (II, I, III and V) in a parallel configuration and a short fifth -strand (IV) antiparallel to the rest of the sheet.…”

Section: Structural Interpretationmentioning

confidence: 77%

“…ADAM-8 is stabilized by three disulfide bridges, similar to ADAM-17 (Mazzola et al, 2008) and ADAM-33 (Orth et al, 2004). In ADAM-8, these disulfide bonds are formed by the following pairs of cysteine residues: Cys310-Cys395, Cys351-Cys379 and Cys353-Cys362 (Fig.…”

Section: Structural Interpretationmentioning

confidence: 99%

Structure of human ADAM-8 catalytic domain complexed with batimastat

et al. 2012

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PDB Reference: ADAM-8-batimastat, 4dd8.The role of ADAM-8 in cancer and inflammatory diseases such as allergy, arthritis and asthma makes it an attractive target for drug development. Therefore, the catalytic domain of human ADAM-8 was expressed, purified and crystallized in complex with a hydroxamic acid inhibitor, batimastat. The crystal structure of the enzyme-inhibitor complex was refined to 2.1 Å resolution. ADAM-8 has an overall fold similar to those of other ADAM members, including a central five-stranded -sheet and a catalytic Zn 2+ ion. However, unique differences within the S1 0 binding loop of ADAM-8 are observed which might be exploited to confer specificity and selectivity to ADAM-8 competitive inhibitors for the treatment of diseases involving this enzyme.

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“…For our studies, X-ray crystal structure of TACE was taken from PDB ID: 3EDZ [35], having resolution of 1.9 . Protein needed to be prepared prior to docking of ligands into its active site.…”

Section: Dockingmentioning

confidence: 99%

Generation of Selective TACE Inhibitors: Ligand and Structure Based Molecular Modeling, Virtual Screening, Counter Pharmacophore Screening to Get Selective Molecules

Bahia¹,

Silakari²

2009

QSAR Comb. Sci.

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This study describes the ligand based as well as structure based molecular modeling and virtual screening of selective tumor necrosis factor-a converting enzyme (TACE) inhibitors. In ligand based molecular modeling, two statistically reliable pharmacophore models HypoA1 and HypoB1 were generated using a same training set of 22 molecules. HypoA1 consists of two hydrogen bond acceptor and three hydrophobic groups whereas HypoB1 consists of one hydrogen bond donor, one ring aromatic and three hydrophobic groups. Virtual screening was performed with both models in in-house database of 1.2 million molecules. To remove non selective hits from screened molecules, a counter pharmacophore was generated using inhibitors of MMP-1, an important enzyme involved in musculoskeletal degradation. In structure based molecular modeling, docking analysis was performed to explore the important interactions between ligands and protein. On comparison, HypoA1 and HypoB1 were found to be complementing with results of docking analysis suggesting high reliability of both models for their use in virtual screening/designing of new molecules.

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Discovery of novel hydroxamates as highly potent tumor necrosis factor-α converting enzyme inhibitors. Part II: Optimization of the S3′ pocket

Cited by 30 publications

References 24 publications

ADAMs 10 and 17 Represent Differentially Regulated Components of a General Shedding Machinery for Membrane Proteins Such as Transforming Growth Factor α, L-Selectin, and Tumor Necrosis Factor α

ADAMs 10 and 17 Represent Differentially Regulated Components of a General Shedding Machinery for Membrane Proteins Such as Transforming Growth Factor α, L-Selectin, and Tumor Necrosis Factor α

Structure of human ADAM-8 catalytic domain complexed with batimastat

Generation of Selective TACE Inhibitors: Ligand and Structure Based Molecular Modeling, Virtual Screening, Counter Pharmacophore Screening to Get Selective Molecules

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