Gollner Andreas, Rudolph Dorothea, Arnhof Heribert, Bauer Markus, Blake Sophia M, Boehmelt Guido, Cockroft Xiao-Ling, Dahmann Georg, Ettmayer Peter, Gerstberger Thomas, Karolyi-Oezguer Jale, Kessler Dirk, Kofink Christiane, Ramharter Juergen, Rinnenthal Jörg, Savchenko Alexander, Schnitzer Renate, Weinstabl Harald, Weyer-Czernilofsky Ulrike, Wunberg Tobias, McConnell Darryl B
Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
Boehringer Ingelheim Pharma GmbH & Co. KG , 88400 Biberach, Germany.
J Med Chem. 2016 Nov 23;59(22):10147-10162. doi: 10.1021/acs.jmedchem.6b00900. Epub 2016 Nov 15.
Scaffold modification based on Wang's pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3'-pyrrolidin]-2(1H)-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-[(3S,3'S,3'aS,5'R,6'aS)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-2-oxo-1,2,3',3'a,4',5',6',6'a-octahydro-1'H-spiro[indole-3,2'-pyrrolo[3,2-b]pyrrole]-5'-yl]benzoic acid (BI-0252).
基于王博士开创性的MDM2-p53抑制剂进行的支架修饰，得到了新型的、化学性质稳定的螺环氧化吲哚化合物，其具有螺[3H-吲哚-3,2'-吡咯烷]-2(1H)-酮支架，不像最初的螺[3H-吲哚-3,3'-吡咯烷]-2(1H)-酮支架那样容易发生差向异构化。受天然产物结构启发进行的进一步基于结构的优化，得到了一个复杂的稠环系统，该系统非常适合与MDM2蛋白结合，并中断其与TP53的蛋白质-蛋白质相互作用（PPI）。这些化合物具有高度选择性，并且在SJSA-1异种移植模型中显示出体内疗效，即使单次给药时也是如此，如4-[(3S,3'S,3'aS,5'R,6'aS)-6-氯-3'-(3-氯-2-氟苯基)-1'-(环丙基甲基)-2-氧代-1,2,3',3'a,4',5',6',6'a-八氢-1'H-螺[吲哚-3,2'-吡咯并[3,2-b]吡咯]-5'-基]苯甲酸（BI-0252）所示。
