Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification.
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.
Coumar
Mohane Selvaraj
MS
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
Chu
Chang-Ying
CY
Lin
Cheng-Wei
CW
Shiao
Hui-Yi
HY
Ho
Yun-Lung
YL
Reddy
Randheer
R
Lin
Wen-Hsing
WH
Chen
Chun-Hwa
CH
Peng
Yi-Hui
YH
Leou
Jiun-Shyang
JS
Lien
Tzu-Wen
TW
Huang
Chin-Ting
CT
Fang
Ming-Yu
MY
Wu
Szu-Huei
SH
Wu
Jian-Sung
JS
Chittimalla
Santhosh Kumar
SK
Song
Jen-Shin
JS
Hsu
John T-A
JT
Wu
Su-Ying
SY
Liao
Chun-Chen
CC
Chao
Yu-Sheng
YS
Hsieh
Hsing-Pang
HP
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
D000970:Antineoplastic Agents; D005663:Furans; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D066246:ErbB Receptors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases