title: Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification.
abstract: A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
authors.forename: Chang-Ying
authors.initials: CY
authors.lastname: Chu
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Lin
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Shiao
authors.forename: Yun-Lung
authors.initials: YL
authors.lastname: Ho
authors.forename: Randheer
authors.initials: R
authors.lastname: Reddy
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.forename: Chun-Hwa
authors.initials: CH
authors.lastname: Chen
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Peng
authors.forename: Jiun-Shyang
authors.initials: JS
authors.lastname: Leou
authors.forename: Tzu-Wen
authors.initials: TW
authors.lastname: Lien
authors.forename: Chin-Ting
authors.initials: CT
authors.lastname: Huang
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Fang
authors.forename: Szu-Huei
authors.initials: SH
authors.lastname: Wu
authors.forename: Jian-Sung
authors.initials: JS
authors.lastname: Wu
authors.forename: Santhosh Kumar
authors.initials: SK
authors.lastname: Chittimalla
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Chun-Chen
authors.initials: CC
authors.lastname: Liao
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D064127:Aurora Kinases; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D066246:ErbB Receptors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases