Article

A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib) Relationships among Protein Conformation, Inhibitor Off-Rate, and Receptor Activity in Tumor Cells

Department of Computational, Analytical and Structural Sciences, GlaxoSmithKline, Inc., Research Triangle Park, North Carolina 27709, USA.
Cancer Research (Impact Factor: 9.33). 10/2004; 64(18):6652-9. DOI: 10.1158/0008-5472.CAN-04-1168
Source: PubMed

ABSTRACT

GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.

  • Source
    • "The biological consequences of the binding of TKIs with EGFR family members are poorly understood, and several researchers are currently examining the different TKIs interactions within the human kinome [156]. In addition, it has been described that TKIs can interact with different dimerization complexes with active or inactive forms of EGFRs [157] [158] [159]. Also, TKIs can modify the amount of EGFR family ligands [122]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2-positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as mono-therapy or combined with other pharmacological agents.
    Full-text · Article · Nov 2015 · American Journal of Cancer Research
  • Source
    • "Recently we reported an effective in silico screening method to isolate candidates that inhibit HBV replication [8]. Besides our study, several researchers have successfully discovered protein targets implicated in various diseases [9] [10], resulting in fierce competition among pharmaceutical companies and other organizations to discover drug-candidate compounds that inhibit or activate these protein targets [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Antiviral therapy for chronic hepatitis B that uses nucleos(t)ide analogue is considered effective. However, most drugs of this class frequently result in viral relapse after cessation of therapy as well as the emergence of resistance, thereby limiting their clinical use. In order to increase the therapeutic efficiency of chronic hepatitis B treatments, it is important to survey novel (chemical) reagents targeting other stages of the viral replication process. The aim of this study was to identify novel capsid inhibitor candidates using in silico screening. We discovered four such candidates that decreased the levels of HBV DNA and HBsAg in vitro. These four capsid inhibitor candidates did not induce cell toxicity even at high concentrations. Results from docking simulation showed that the candidates bounded with high affinity with the capsid protein hydrophobic binding site. Identifying direct acting HBV core protein inhibitors increases the likelihood that novel medicines can be developed that allows the combination of novel anti-viral drugs and nucleos(t)ide analogue or interferon for HBV treatment. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Biochemical and Biophysical Research Communications
  • Source
    • "The EGFR template was prepared from a crystal structure of EGFR bound with lapatinib (PDB code 1XKK) (Wood et al., 2004). Bound lapatinib and all water molecules were removed, all polar hydrogen parameter were added and nonpolar hydrogens of 1XKK were merged before adding Gasteiger Huckel charges by AutoDockTools (ADT) 1.5.6 (Huey et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A small molecule EGFR inhibitor, 4-(2-(3-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)ureido)vinyl)-1,2-phenylene diacetate (CIU1) was designed in silico by using caffeic scaffold as core structure. The designed compound showed anti-proliferative action against different solid tumor cell lines, particularly metastatic breast cancer cells. CIU1 inhibited the growth of EGFR-overexpressing MDA-MB-468 triple-negative breast cancer cells and wild-type non-small-cell lung cancer H460 cells with IC50 values of 8.96 μM and 12.98 μM, respectively, these anti-proliferative effects of CIU1 were comparable to gefitinib (a specific EGFR inhibitor) or lapatinib (a dual EGFR and HER2 tyrosine kinase inhibitor). Interestingly CIU1 effectively inhibited the invasive hormone-dependent MCF-7 cancer cells with an IC50 2.34 μM. The immunoblot analyses revealed that CIU1 induced apoptosis and suppressed EGFR expression in EGFR-overexpressing breast cancer (MDA-MB468) and lung cancer (PC-9) cells. The findings substantiated our design strategy and demonstrated the potential of CIU1 as new lead for further optimization in the development of anticancer drugs against advanced solid tumors.
    Full-text · Article · Jun 2015 · Journal of applied biomedicine
Show more