2. Academic Validation
  3. Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification

Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification

  • J Med Chem. 2010 Jul 8;53(13):4980-8. doi: 10.1021/jm1000198.
Mohane Selvaraj Coumar 1,  Chang-Ying Chu,  Cheng-Wei Lin,  Hui-Yi Shiao,  Yun-Lung Ho,  Randheer Reddy,  Wen-Hsing Lin,  Chun-Hwa Chen,  Yi-Hui Peng,  Jiun-Shyang Leou,  Tzu-Wen Lien,  Chin-Ting Huang,  Ming-Yu Fang,  Szu-Huei Wu,  Jian-Sung Wu,  Santhosh Kumar Chittimalla,  Jen-Shin Song,  John T-A Hsu,  Su-Ying Wu,  Chun-Chen Liao,  Yu-Sheng Chao,  Hsing-Pang Hsieh
Affiliations

Affiliation

  • 1 Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
PMID: 20550212 DOI: 10.1021/jm1000198
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18213
    98.84%, EGFR 抑制剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z