title: Structural insights into the design of nonpeptidic isothiazolidinone-containing inhibitors of protein-tyrosine phosphatase 1B.
abstract: Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe(182) of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular pi-stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail.
authors.affiliation: Incyte Corporation, Wilmington, Delaware 19880, USA. pauljala@gmail.com
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ala
authors.forename: Lucie
authors.initials: L
authors.lastname: Gonneville
authors.forename: Milton
authors.initials: M
authors.lastname: Hillman
authors.forename: Mary
authors.initials: M
authors.lastname: Becker-Pasha
authors.forename: Eddy W
authors.initials: EW
authors.lastname: Yue
authors.forename: Brent
authors.initials: B
authors.lastname: Douty
authors.forename: Brian
authors.initials: B
authors.lastname: Wayland
authors.forename: Padmaja
authors.initials: P
authors.lastname: Polam
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Crawley
authors.forename: Erin
authors.initials: E
authors.lastname: McLaughlin
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sparks
authors.forename: Brian
authors.initials: B
authors.lastname: Glass
authors.forename: Amy
authors.initials: A
authors.lastname: Takvorian
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burn
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Hollis
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008958:Models, Molecular; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013844:Thiazoles; C512915:isothiazolidinone; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases