Discovery and Optimization of Quinolinone Derivatives as Potent, Selective and Orally Bioavailable mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.

@article{Lin2019DiscoveryAO,
  title={Discovery and Optimization of Quinolinone Derivatives as Potent, Selective and Orally Bioavailable mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.},
  author={Jian Shiun Lin and Wei Lu and Justin Andrew Caravella and Ann M. Campbell and Robert B Diebold and Anna Ericsson and Edward Fritzen and Gary R Gustafson and David R. Lancia and Tatiana Shelekhin and Zhongguo Wang and Jennifer Katiusca Castro and Andrea Clarke and Deepali Gotur and Helen R. Josephine and Marie Katz and Hien Diep and Mark T. Kershaw and Lili Yao and Goss Stryker Kauffman and Stephen E Hubbs and George P. Luke and Angela V. Toms and Liann Wang and Kenneth W. Bair and Kenneth Jay Barr and Christopher J. Dinsmore and Duncan Walker and Susan Plainsboro Ashwell},
  journal={Journal of medicinal chemistry},
  year={2019}
}
Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild type IDH1. The X-ray structure… CONTINUE READING