Original article Towards predictive inhibitor design for the EGFR autophosphorylation activity Amor A. San Juan a,b, * a Life Science Division, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea b School of Science, University of Science and Technology, 52 Eoeun-dong, Yuseong-gu, Daejeon 305-333, South Korea Received 25 January 2007; received in revised form 13 June 2007; accepted 15 June 2007 Available online 5 July 2007 Abstract Inhibition of the epidermal growth factor receptor (EGFR) tyrosine kinase is one among the pivotal targets for the treatment of cancer. The structural investigation directly halting the EGFR autophosphorylation is expected to give insights into alternatively blocking the aberrant ac- tivity of EGFR. The three-dimensional quantitative structureeactivity relationship (3D-QSAR) models were developed from the systematic search conformer-based alignment method. Models derived from the training set of 95 compounds showed superior CoMFA as compared with CoMSIA (CoMFA: q 2 ¼ 0.50, r 2 ¼ 0.74, N ¼ 5, F ¼ 48.83, r 2 pred ¼ 0.56 while CoMSIA: q 2 ¼ 0.48, r 2 ¼ 0.62, N ¼ 2, F ¼ 72.70, r 2 pred ¼ 0.51). Validation of the models by test set prediction of 26 compounds was in good agreement with the experimental results. Further validation by molecular docking superimposition into the 3D-QSAR contour maps was found in agreement with each other. We identified that the structural modification of compound 19 by attachment of a bulky group on pyrrole ring along with an electronegative group on quinazo- line ring and a hydrogen-bond donor on methyl formate opens a new avenue towards the optimization of novel chemical entities to develop potent inhibitors for EGFR autophosphorylation. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: 3D-QSAR; Autophosphorylation; EGFR; Ligand design; Lung cancer 1. Introduction The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase (RTK) discovered [1]. EGFR family (EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/ HER4) is composed of an extracellular ligand-binding domain, followed by a single transmembrane domain and a cytoplasmic domain containing a conserved protein tyrosine kinase [2]. EGFR, ErbB2 and ErbB4 contain the catalytically competent ki- nase domains and can form heterodimers with each other [3]. ErbB3 contains an inactive kinase domain, but it can pair with and activate the other members of the family [3]. The critical roles of EGFR members include the regulation of cell prolifer- ation, differentiation and migration [4]. The binding of EGFR to its cognate ligands leads to autophosphorylation of RTK fol- lowed by the activation of signal transduction pathways [5]. Ap- parently, the abnormal activation of EGFR is over-expressed in several cancers: non-small-cell lung, breast, colorectal, bladder, prostate and ovary [6,7]. EGFR was found abundantly expressed in most patients with non-small-cell lung cancer (NSCLC) [8]. Molecular targeted therapies approved for EGFR aberrant activity include the anti-cancer drugs erlotinib (Tarceva; OSI Pharmaceuticals) and gefitinib (Iressa; Astra-Zeneca Pharma- ceuticals). Gefitinib and erlotinib are quinazoline-based EGFR inhibitors which reversibly prevent the ATP binding and auto- phosphorylation activity [9e11]. The clinical development of gefitinib has proved to be more problematic due to toxic side effects but erlotinib achieved breakthrough in trials [12]. * Corresponding address. Life Science Division, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea. Tel.: þ82 2 958 6850. E-mail address: amor.san_juan@up.edu.ph 0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2007.06.006 Available online at www.sciencedirect.com European Journal of Medicinal Chemistry 43 (2008) 781e791 http://www.elsevier.com/locate/ejmech