Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts

Roben Gieling; Muhammad Babur; Lupti Mamnani; Natalie Burrows; Brian Telfer; Fabrizio Carta; Jean-Yves Winum; Andrea Scozzafava; Claudiu Supuran; Kaye Williams

doi:10.1021/jm300529u

Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts

Roben Gieling, Muhammad Babur, Lupti Mamnani, Natalie Burrows, Brian Telfer, Fabrizio Carta, Jean-Yves Winum, Andrea Scozzafava, Claudiu Supuran, Kaye Williams

Applied Sciences Department

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Abstract

A panel of compounds belonging to the underexposed sulfamate class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was generated that displayed high specificity at nanomolar levels for the tumor-associated CA IX/XII isoforms. Three of the specific CA IX/XII inhibitors showed a positive response in in vitro assays for tumor cell migration and spreading. One of them, 4-(3′-(3″,5″-dimethylphenyl)ureido)phenyl sulfamate (S4), was taken forward into the orthotopic MDA-MB-231 (breast carcinoma) model in mice. Treatment with a 10 mg/kg maintenance dosage of S4 given daily on a “5 days on, 2 days off” regimen reduced metastatic tumor burden in the lung while not affecting primary tumor growth or mouse condition. CA inhibitors of the sulfamate class specifically targeting the tumor-associated isoforms are potential candidates in antimetastatic therapy.

Original language	English
Pages (from-to)	5591-55600
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	11
DOIs	https://doi.org/10.1021/jm300529u
Publication status	Published - 14 Jun 2012

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title = "Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts",

abstract = "A panel of compounds belonging to the underexposed sulfamate class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was generated that displayed high specificity at nanomolar levels for the tumor-associated CA IX/XII isoforms. Three of the specific CA IX/XII inhibitors showed a positive response in in vitro assays for tumor cell migration and spreading. One of them, 4-(3′-(3″,5″-dimethylphenyl)ureido)phenyl sulfamate (S4), was taken forward into the orthotopic MDA-MB-231 (breast carcinoma) model in mice. Treatment with a 10 mg/kg maintenance dosage of S4 given daily on a “5 days on, 2 days off” regimen reduced metastatic tumor burden in the lung while not affecting primary tumor growth or mouse condition. CA inhibitors of the sulfamate class specifically targeting the tumor-associated isoforms are potential candidates in antimetastatic therapy.",

author = "Roben Gieling and Muhammad Babur and Lupti Mamnani and Natalie Burrows and Brian Telfer and Fabrizio Carta and Jean-Yves Winum and Andrea Scozzafava and Claudiu Supuran and Kaye Williams",

year = "2012",

month = jun,

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doi = "10.1021/jm300529u",

language = "English",

volume = "55",

pages = "5591--55600",

journal = "Journal of Medicinal Chemistry",

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TY - JOUR

T1 - Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts

AU - Gieling, Roben

AU - Babur, Muhammad

AU - Mamnani, Lupti

AU - Burrows, Natalie

AU - Telfer, Brian

AU - Carta, Fabrizio

AU - Winum, Jean-Yves

AU - Scozzafava, Andrea

AU - Supuran, Claudiu

AU - Williams, Kaye

PY - 2012/6/14

Y1 - 2012/6/14

N2 - A panel of compounds belonging to the underexposed sulfamate class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was generated that displayed high specificity at nanomolar levels for the tumor-associated CA IX/XII isoforms. Three of the specific CA IX/XII inhibitors showed a positive response in in vitro assays for tumor cell migration and spreading. One of them, 4-(3′-(3″,5″-dimethylphenyl)ureido)phenyl sulfamate (S4), was taken forward into the orthotopic MDA-MB-231 (breast carcinoma) model in mice. Treatment with a 10 mg/kg maintenance dosage of S4 given daily on a “5 days on, 2 days off” regimen reduced metastatic tumor burden in the lung while not affecting primary tumor growth or mouse condition. CA inhibitors of the sulfamate class specifically targeting the tumor-associated isoforms are potential candidates in antimetastatic therapy.

AB - A panel of compounds belonging to the underexposed sulfamate class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was generated that displayed high specificity at nanomolar levels for the tumor-associated CA IX/XII isoforms. Three of the specific CA IX/XII inhibitors showed a positive response in in vitro assays for tumor cell migration and spreading. One of them, 4-(3′-(3″,5″-dimethylphenyl)ureido)phenyl sulfamate (S4), was taken forward into the orthotopic MDA-MB-231 (breast carcinoma) model in mice. Treatment with a 10 mg/kg maintenance dosage of S4 given daily on a “5 days on, 2 days off” regimen reduced metastatic tumor burden in the lung while not affecting primary tumor growth or mouse condition. CA inhibitors of the sulfamate class specifically targeting the tumor-associated isoforms are potential candidates in antimetastatic therapy.

U2 - 10.1021/jm300529u

DO - 10.1021/jm300529u

M3 - Article

SN - 0022-2623

VL - 55

SP - 5591

EP - 55600

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -

Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts

Abstract

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