Direct NMR Probing of Hydration Shells of Protein Ligand Interfaces and Its Application to Drug Design

Fragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology (LOGSY titration) that allows the determination of binding modes of low affinity binders in the protein–ligand interface and reveals suitable ligand positions for the addition of functional groups that either address or substitute protein-bound water, information of utmost importance for drug design. The particular benefit of the methodology and in contrast to conventional ligand-based methods is the independence of the molecular weight of the protein under study. The validity of the novel approach is demonstrated on two ligands interacting with bromodomain 1 of bromodomain containing protein 4, a prominent cancer target in pharmaceutical industry

Discovery of Novel Spiro[3<i>H</i>‑indole-3,2′-pyrrolidin]-2(1<i>H</i>)‑one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2–p53 Interaction

Scaffold modification based on Wang’s pioneering MDM2–p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro­[3<i>H</i>-indole-3,2′-pyrrolidin]-2­(1<i>H</i>)-one scaffold that are not prone to epimerization as observed for the initial spiro­[3<i>H</i>-indole-3,3′-pyrrolidin]-2­(1<i>H</i>)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein–protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3<i>S</i>,3′<i>S</i>,3′a<i>S</i>,5′<i>R</i>,6′a<i>S</i>)-6-chloro-3′-(3-chloro-2-fluorophenyl)-1′-(cyclopropylmethyl)-2-oxo-1,2,3′,3′a,4′,5′,6′,6′a-octahydro-1′<i>H</i>-spiro­[indole-3,2′-pyrrolo­[3,2-<i>b</i>]­pyrrole]-5′-yl]­benzoic acid (BI-0252)

Discovery of Novel Spiro[3<i>H</i>‑indole-3,2′-pyrrolidin]-2(1<i>H</i>)‑one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2–p53 Interaction

Scaffold modification based on Wang’s pioneering MDM2–p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro­[3<i>H</i>-indole-3,2′-pyrrolidin]-2­(1<i>H</i>)-one scaffold that are not prone to epimerization as observed for the initial spiro­[3<i>H</i>-indole-3,3′-pyrrolidin]-2­(1<i>H</i>)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein–protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3<i>S</i>,3′<i>S</i>,3′a<i>S</i>,5′<i>R</i>,6′a<i>S</i>)-6-chloro-3′-(3-chloro-2-fluorophenyl)-1′-(cyclopropylmethyl)-2-oxo-1,2,3′,3′a,4′,5′,6′,6′a-octahydro-1′<i>H</i>-spiro­[indole-3,2′-pyrrolo­[3,2-<i>b</i>]­pyrrole]-5′-yl]­benzoic acid (BI-0252)