Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine aurora kinase inhibitor

Hui Yi Shiao, Mohane Selvaraj Coumar, Chun Wei Chang, Yi Yu Ke, Ya Hui Chi, Chang Ying Chu, Hsu Yi Sun, Chun Hwa Chen, Wen Hsing Lin, Ka Shu Fung, Po Chu Kuo, Chin Ting Huang, Kai Yen Chang, Cheng Tai Lu, John T.A. Hsu, Chiung Tong Chen, Weir Torn Jiaang, Yu Sheng Chao, Hsing Pang Hsieh

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Ligand efficiency (LE) and lipophilic efficiency (LipE) are two important indicators of "drug-likeness", which are dependent on the molecule's activity and physicochemical properties. We recently reported a furano-pyrimidine Aurora kinase inhibitor 4 (LE = 0.25; LipE = 1.75), with potent activity in vitro; however, 4 was inactive in vivo. On the basis of insights obtained from the X-ray co-crystal structure of the lead 4, various solubilizing functional groups were introduced to optimize both the activity and physicochemical properties. Emphasis was placed on identifying potential leads with improved activity as well as better LE and LipE by exercising tight control over the molecular weight and lipophilicity of the molecules. Rational optimization has led to the identification of Aurora kinase inhibitor 27 (IBPR001; LE = 0.26; LipE = 4.78), with improved in vitro potency and physicochemical properties, resulting in an in vivo active (HCT-116 colon cancer xenograft mouse model) anticancer agent.

Original languageEnglish
Pages (from-to)5247-5260
Number of pages14
JournalJournal of Medicinal Chemistry
Volume56
Issue number13
DOIs
Publication statusPublished - 2013 Jul 11

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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