Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of albumin binding.

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Sheppard GS, Wang J, Kawai M, Fidanze SD, BaMaung NY, Erickson SA, Barnes DM, Tedrow JS, Kolaczkowski L, Vasudevan A, Park DC, Wang GT, Sanders WJ, Mantei RA, Palazzo F, Tucker-Garcia L, Lou P, Zhang Q, Park CH, Kim KH, Petros A, Olejniczak E, Nettesheim D, Hajduk P, Henkin J, Lesniewski R, Davidsen SK, Bell RL

Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of albumin binding.

J Med Chem. 2006 Jun 29;49(13):3832-49.

PubMed ID
16789740 [ View in PubMed
]
Abstract

Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening. These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays. Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
MethionineMethionine aminopeptidase 2ProteinHumans
Unknown
Product of
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
2-[({2-[(1Z)-3-(DIMETHYLAMINO)PROP-1-ENYL]-4-FLUOROPHENYL}SULFONYL)AMINO]-5,6,7,8-TETRAHYDRONAPHTHALENE-1-CARBOXYLIC ACIDMethionine aminopeptidase 2IC 50 (nM)197.422Details
2-[(PHENYLSULFONYL)AMINO]-5,6,7,8-TETRAHYDRONAPHTHALENE-1-CARBOXYLIC ACIDMethionine aminopeptidase 2IC 50 (nM)107.422Details
5-METHYL-2-[(PHENYLSULFONYL)AMINO]BENZOIC ACIDMethionine aminopeptidase 2IC 50 (nM)14007.422Details