1429383-27-6Relevant articles and documents
Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction
Gonzalez, Ana Z.,Eksterowicz, John,Bartberger, Michael D.,Beck, Hilary P.,Canon, Jude,Chen, Ada,Chow, David,Duquette, Jason,Fox, Brian M.,Fu, Jiasheng,Huang, Xin,Houze, Jonathan B.,Jin, Lixia,Li, Yihong,Li, Zhihong,Ling, Yun,Lo, Mei-Chu,Long, Alexander M.,McGee, Lawrence R.,McIntosh, Joel,McMinn, Dustin L.,Oliner, Jonathan D.,Osgood, Tao,Rew, Yosup,Saiki, Anne Y.,Shaffer, Paul,Wortman, Sarah,Yakowec, Peter,Yan, Xuelei,Ye, Qiuping,Yu, Dongyin,Zhao, Xiaoning,Zhou, Jing,Olson, Steven H.,Medina, Julio C.,Sun, Daqing
, p. 2472 - 2488 (2014/04/17)
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
Rational design and binding mode duality of MDM2-p53 inhibitors
De Turiso, Felix Gonzalez-Lopez,Sun, Daqing,Rew, Yosup,Bartberger, Michael D.,Beck, Hilary P.,Canon, Jude,Chen, Ada,Chow, David,Correll, Tiffany L.,Huang, Xin,Julian, Lisa D.,Kayser, Frank,Lo, Mei-Chu,Long, Alexander M.,McMinn, Dustin,Oliner, Jonathan D.,Osgood, Tao,Powers, Jay P.,Saiki, Anne Y.,Schneider, Steve,Shaffer, Paul,Xiao, Shou-Hua,Yakowec, Peter,Yan, Xuelei,Ye, Qiuping,Yu, Dongyin,Zhao, Xiaoning,Zhou, Jing,Medina, Julio C.,Olson, Steven H.
, p. 4053 - 4070 (2013/06/27)
Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC 50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21WAF1 mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.
