2 research outputs found
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 spiroÂ[3<i>H</i>-indole-3,2′-pyrrolidin]-2Â(1<i>H</i>)-one scaffold that are not prone to epimerization as observed
for the initial spiroÂ[3<i>H</i>-indole-3,3′-pyrrolidin]-2Â(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>-spiroÂ[indole-3,2′-pyrroloÂ[3,2-<i>b</i>]Âpyrrole]-5′-yl]Âbenzoic 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 spiroÂ[3<i>H</i>-indole-3,2′-pyrrolidin]-2Â(1<i>H</i>)-one scaffold that are not prone to epimerization as observed
for the initial spiroÂ[3<i>H</i>-indole-3,3′-pyrrolidin]-2Â(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>-spiroÂ[indole-3,2′-pyrroloÂ[3,2-<i>b</i>]Âpyrrole]-5′-yl]Âbenzoic acid (BI-0252)