The discovery of novel tartrate-based TNF-α converting enzyme (TACE) inhibitors

Rösner, K; Guo, Zhuyan; Orth, Peter; Shipps, Gerald W.; Belanger, David; Chan, Tin Yau; Curran, Patrick J.; Dai, Chaoyang; Deng, Yongqi; Girijavallabhan, Vinay; Hong, Liwu; Lavey, Brian J.; Lee, Joe F.; Li, Dansu; Liu, Zhidan; Popovici‐Muller, Janeta; Ting, Pauline C.; Vaccaro, Henry; Wang, Li; Wang, Tong; Yu, Wei; Zhou, Guowei; Niu, Xiaoda; Sun, Jing; Kozlowski, Joseph A.; Lundell, Daniel; Madison, Vincent; McKittrick, Brian A.; Piwinski, John J.; Shih, Neng Yang; Siddiqui, M. Arshad; Strickland, Corey

doi:10.1016/j.bmcl.2009.12.004

Cited by 26 publications

(20 citation statements)

References 25 publications

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“…There is, however, a paucity of substrates that interact with exosites of ADAMs of interest. Knowledge of ADAMs exosites is also limited, as structural information is primarily limited to ADAM catalytic domains 34–36 . Current methods to identify exosite-binding substrates and exosites themselves are laborious 37 or in early stages of development 38 .…”

Section: Discusssionmentioning

confidence: 99%

Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate

Madoux

Dreymüller

Pettiloud

et al. 2016

Sci Rep

119

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ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection. As a result of this uHTS effort, a selective, time-dependent, non-zinc-binding inhibitor of ADAM10 with Ki = 883 nM was discovered. This compound exhibited low cell toxicity and was able to selectively inhibit shedding of known ADAM10 substrates in several cell-based models. We hypothesize that differential glycosylation of these cognate substrates is the source of selectivity of our novel inhibitor. The data indicate that this novel inhibitor can be used as an in vitro and, potentially, in vivo, probe of ADAM10 activity. Additionally, results of the present and prior studies strongly suggest that glycosylated substrate are applicable as screening agents for discovery of selective ADAM probes and therapeutics.

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Section: Discusssionmentioning

confidence: 99%

Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate

Madoux

Dreymüller

Pettiloud

et al. 2016

Sci Rep

119

View full text Add to dashboard Cite

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“…S1′ loop in TACE and related MMPs showing conformational flexibility that leads to selectivity. (A) TACE structure 2FV5 (cyan) shows significant movement in the S1′ loop (red oval) to accommodate the larger quinolone ring of the 2FV5(91) inhibitor relative to the 3KMC(92) (orange) structure. (B) Overlays of TACE and MMP structures with the ligand from 2FV5 for reference showing side chains proximate to the quinolone ring in space filling representation.…”

Section: Structure-based Selectivity Design Considerationsmentioning

confidence: 99%

Rational Approaches to Improving Selectivity in Drug Design

Huggins

Sherman

Tidor³

2012

J. Med. Chem.

288

265

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“…The chlorophenyl group appeared disordered and lacks 2fofc electron density. [28] The compound was unable to bind properly to the subsite and behave indifferently from other analogues of the series. Likewise, shortening of ethylene linker to the methylene linker resulted into significantly less active compound 24 compared to compound 21.…”

Section: Resultsmentioning

confidence: 99%

“…In view of this, Rosner, et al . [28] have screened their proprietary mixture-based combinatorial library with the automated ligand identification system[29–31] and were able to identify four compounds (Compound. 1-4; Table 1, fig.…”

mentioning

confidence: 99%

“…A novel series of compounds, able to undergo such interactions, were further prepared and evaluated for their binding affinity ( K i ) for TACE. [28] However this study, being sort of structure-activity relationship (SAR), was targeted at the alterations of substituents at different positions and provided no rationale to reduce the trial-and-error factors. Hence, the present communication is aimed at to perform a 2D quantitative structure-activity relationship (2D QSAR) for the reported compounds so as to provide the rationale for drug-design and to grasp some molecular features of the compounds for the property study relating to their binding affinity for TACE.…”

mentioning

confidence: 99%

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Molecular Descriptors in Modelling the Tumour Necrosis Factor-α Converting Enzyme Inhibition Activity of Novel Tartrate-Based Analogues

Singh¹

2013

Indian J Pharm Sci

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The tumour necrosis factor-α converting enzyme inhibition activity of a series comprising of novel tartrate-based analogues has been quantitatively analysed in terms of molecular descriptors. The statistically validated quantitative structure-activity relationship models provided rationales to explain the inhibition activity of these congeners. The descriptors identified through combinatorial protocol in multiple linear regression analysis have highlighted the role of Moran autocorrelation of lag 7, weighted by atomic van der Waals volume, presence of both prime and nonprime amide carbonyl oxygen in the tartrate moiety and occurrence of five membered ring bearing substituents at varying sites. A few potential novel tartrate-based analogues have been suggested for further investigation.

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The discovery of novel tartrate-based TNF-α converting enzyme (TACE) inhibitors

Cited by 26 publications

References 25 publications

Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate

Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate

Rational Approaches to Improving Selectivity in Drug Design

Molecular Descriptors in Modelling the Tumour Necrosis Factor-α Converting Enzyme Inhibition Activity of Novel Tartrate-Based Analogues

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