- Discovery of linear unnatural peptides as potent mutant isocitrate dehydrogenase 1 inhibitors by Ugi reaction
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Isocitrate dehydrogenases 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to ɑ-ketoglutaric acid (α-KG). It is the most frequently mutated metabolic gene in human cancer and its mutations interfere with cell metabolism and epigenetic regulation, thus promoting tumorigenesis. In order to discover potent new mutant IDH1 inhibitors, based on the structure of marketed inhibitor AG-120 (Ivosidenib), we designed, synthesized and evaluated a series of linear unnatural peptide analogues via Ugi reaction, as potential mutant IDH1 inhibitors. All these compounds were evaluated for their inhibition on mutant IDH1 enzyme activity. The structure-activity relationship was discussed on the basis of experimental data, with an attempt to pave the way for future studies. Among them, 43 exhibited potent and selective enzyme inhibitory activity, and showed strong binding affinity with mutant IDH1. It can decrease the cellular concentration of 2-HG, and suppress the proliferation of HT1080 and IDH1 mutant-U-87 cells by selectively inhibiting the activity of mutant IDH1.
- Zhou, Xuechen,Zheng, Mengzhu,Zhao, Na,Hu, Yixin,Yang, Kaiyin,Huo, Junfeng,Liu, Guangyuan,Huang, Jiangeng,Chen, Lixia,Zhou, Yirong,Li, Hua
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- Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo
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Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ~90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.
- Popovici-Muller, Janeta,Saunders, Jeffrey O.,Salituro, Francesco G.,Travins, Jeremy M.,Yan, Shunqi,Zhao, Fang,Gross, Stefan,Dang, Lenny,Yen, Katharine E.,Yang, Hua,Straley, Kimberly S.,Jin, Shengfang,Kunii, Kaiko,Fantin, Valeria R.,Zhang, Shunan,Pan, Qiongqun,Shi, Derek,Biller, Scott A.,Su, Shinsan M.
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supporting information
p. 850 - 855
(2013/01/15)
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- THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHOD OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 121
(2012/02/02)
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