Abstract
Insulin-like growth factor-1 receptor (IGF1R) is one of receptor tyrosine kinase that plays a significant role in cancer and has been pursued as drug target for cancer therapy. Molecular docking and comparative molecular field analysis (CoMFA) studies were carried out on the series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines IGF1R inhibitors. The conformations of these inhibitors from docking results provided a reliable conformational alignment scheme for 3D QSAR model. Based on these conformations, significant CoMFA model was performed with a leave-one-out cross-validated q 2 of 0.590. The noncross-validated analysis revealed r 2 value of 0.941, F = 34.882, and an estimated standard error of 0.178 with four optimum components. The predictive ability of our model was validated by the testing set with a conventional r 2 value of 0.925. The effective model may be used to design more potent IGF1R inhibitors and predict their activities before synthesis or experimental test.
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References
Baxter CA, Murray CW, Clark DE (1998) Flexible docking using Tabu search and an empirical estimate of binding affinity. Proteins 33:367–382
Bush BL, Nachbar RB (1993) Sample-distance partial least squares: PLS optimized for many variables, with application to CoMFA. J Comput Aided Mol Des 7:587–619
Clark MC, Cramer RD, Opdenbosch NV (1989) Validation of the General Purpose Tripose 5.2 Force Field. J Comput Chem 10:982–1012
Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE (2005) Molecular interactions of the IGF system. Cytokine Growth Factor Rev 16:421–439
Eldridge MD, Murray CW, Auton TR, Paolini GV, Mee RP (1997) Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J Comput Aided Mol Des 11:425–445
Gary TW, Robert AM, Robert DH (2010) Substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as multi-targeted inhibitors of insulin-like growth factor-1 receptor (IGF1R) and members of ErbB-family receptor kinases. Bioorg Med Chem Lett 10:6067–6071
Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron 36:3219–3228
Grothey A, Voigt W, Schober C, Muller T, Dempke W, Schmoll HJ (1999) The role of insulin-like growth factor I and its receptor in cell growth, transformation, apoptosis, and chemoresistance in solid tumors. J Cancer Res Clin Oncol 125:166–173
Haluska P, Shaw HM, Batzel GN, Yin D, Molina JR, Molife LR, Yap TA, Roberts ML, Sharma A, Gualberto A, Adjei AA, de-Bono JS (2007) Phase I dose escalation study of the anti-insulin-like growth factor-I receptor monoclonal antibody CP-751, 871 in patients with refractory solid tumors. Clin Cancer Res 13:5834–5840
Hidalgo M, Tirado GM, Lewis N, Vuky JL, Taylor G, Hayburn JL, Hsu K, Kosh M, Picozzi VJ (2008) A phase I study of MK-0646, a humanized monoclonal antibody against the insulin-like growth factor receptor type 1 (IGF1R) in advanced solid tumor patients in a q2 wk schedule. J Clin Oncol ASCO Annu Meet Proc abstract# 3520
Higano CS, Yu YE, Whiting SH, et al. (2007) A phase I, first in man study of weekly IMC A-12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumours. ASCO annual meeting proceedings Part I. J Clin Oncol 25(18S)(June 20 Suppl):3505
Hynes N, Lane H (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354
Li R, Pourpak A, Morris SW (2009) Inhibition of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase as a novel cancer therapy approach. J Med Chem 52:4981–5004
Moreau P, Hulin C, Facon T, Boccadoro M, Mery MD, Deslandes A, Harousseau JL (2007) Phase I study of AVE1642 anti IGF-1R monoclonal antibody in patients with advanced multiple myeloma. Blood 110(11):1166 (ASH annual meeting abstracts)
Muddassar M, Pasha FA, Chung HW, Yoo KH, Oh CH, Cho SJ (2008) Receptor guided 3D-QSAR: a useful approach for designing of IGF-1R inhibitors. J Biomed Biotechnol 2008:837653
Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928
Resnik JL, Reichart DB, Huey K, Webster NJ, Seely BL (1998) Elevated insulin-like growth factor I receptor autophosphorylation and kinase activity in human breast cancer. Cancer Res 58:1159–1164
Rothenberg M, Poplin E, Sandler A, Rubin E, Fox F, Schwartz J, Vermeulen W, Youssoufian H (2007) Phase I dose escalation study of the anti-IGF-IR recombinant human IgG1 monoclonal antibody (Mab) IMC-A12, administered every other week to patients with advanced solid tumors. AACR meet abstr no. C84
Sachdev D, Yee D (2007) Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 6:1–12
Timo H, Ulrich G, Henning B, Andree B, Adam S (2010) Allosteric IGF-1R inhibitors. Med Chem Lett 1:199–203
Tolcher AW, Rothenberg ML, Rodon J, Delbeke D, Patnaik A, Nguyen L, Young F, Hwang Y, Haqq C, Puzanov I (2009) Phase I pharmacokinetic and pharmacodynamics study of AMG 479, a fully human monoclonal antibody against insulin-like growth factor receptor 1. J Clin Oncol 27(34):5800–5807
Turner BC, Haffty BG, Narayanan L, Yuan J, Havre PA, Gumbs AA, Kaplan L, Burgaud JL, Carter D, Baserga R, Glazer PM (1997) Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer Res 57:3079–3083
Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein-ligand docking using GOLD. Proteins 52:609–623
Werner H, LeRoith D (1996) The role of the insulin-like growth factor system in human cancer. Adv Cancer Res 68:183–223
Yuli W, Yi S (2002) Insulin-like growth factor receptor-1 as an anti-cancer target: blocking transformation and inducing apoptosis. Curr Cancer Drug Targets 2:191–207
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The authors thank Dr. Zhaoyun Liu for critical evaluation of the manuscript.
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Li, YS., Zhou, L. & Ma, X. Molecular docking and 3D QSAR studies of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as insulin-like growth factor-1 receptor (IGF1R) inhibitors. Med Chem Res 21, 3301–3311 (2012). https://doi.org/10.1007/s00044-011-9877-9
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DOI: https://doi.org/10.1007/s00044-011-9877-9