Irreversible inhibition of epidermal growth factor receptor tyrosine kinase with In Vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785) (original) (raw)
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Evaluation of Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Breast Cancer Research and Treatment, 2004
The epidermal growth factor system is a well characterized growth factor receptor pathway, the deregulation of which has been be associated with neoplastic growth. Overexpression or amplification of the epidermal growth factor receptor (EGFR) or one of its ligands has been linked with the malignant transformation of cells and is correlated with poor prognosis in patients. PD 153035, a quinazoline, has been shown to inhibit the tyrosine kinase activity of EGFR by blocking ATP binding (Fry et al., Science 265: 1093-1095. We set out to determine whether the growth inhibition caused by this agent and five related compounds is a direct result of the blocking of EGFR signaling. The effects on cell proliferation produced by these agents were tested on several tumor cell lines and EC50 values obtained. The EGF responsive cell lines A-431 and MDA-MB-468 exhibit EC50 values of 3 and 6.7 µM, respectively, for PD 153035 which was found to be the most potent. The agents were then tested for their ability to block the paradoxical high dose EGF induced inhibition of A-431 and MDA-MB-468 cell growth as well as EGF induced phosphorylation in A-431 cells. These compounds are able to completely block the effects of exogenously added EGF at 0.5 µM or less. However, higher doses (EC50's ≥ 2 µM) were needed to block the growth of human tumor cell lines potentially implicating a second site of action for these compounds.
Cancer research, 2001
Several inhibitors of EGF receptor (EGFR) tyrosine kinase activity have been developed that compete with ATP at its binding site such as the quinazolines PD 153035 and ZD 1839 or the 4,5-dianilino-phthalimides DAPH1 and DAPH2. When tested on human A431 cells, the quinazolines completely blocked EGF-induced receptor phosphorylation at 100 nM, whereas it was inhibited by DAPH1 and DAPH2 by only 20% at 3 microM. Quinazoline-treated A431 as well as tumor cells expressing less EGFR (A549, MDA MB 231, and T47D) bound 3- to 6-fold more (125)I-labeled EGF than untreated intact control cells. Scatchard analysis revealed the disappearance of low- and high-affinity EGFR on A431 cells upon PD 153035 treatment. A single receptor class of intermediate ligand binding affinity emerged and its number corresponded to the sum of the two classes. DAPH1 and DAPH2 did not change ligand binding properties of EGFR. PD 153035 exerted the most potent effects on EGF binding to A431 or on inhibiting EGF-stimul...
Rational bases for the development of EGFR inhibitors for cancer treatment
The International Journal of Biochemistry & Cell Biology, 2007
Growth factor receptors and their ligands not only regulate normal cell processes but have been also identified as key regulators of human cancer formation. The epidermal growth factor receptor (EGFR/ErbB1/HER1) belongs to the ErbB/HER-family of tyrosine kinase receptors (RTKs). These trans-membrane proteins are activated following binding with peptide growth factors of the EGFfamily of proteins. Several evidences suggest that cooperation of multiple ErbB receptors and ligands is required for the induction of cell transformation. In this respect, EGFR, upon activation, sustains a complex and redundant network of signal transduction pathways with the contribution of other trans-membrane receptors. EGFR has been found to be expressed and altered in a variety of malignancies and clearly it plays a significant role in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. Moreover, amplification of the EGFR gene and mutations in the EGFR tyrosine kinase domain have been recently reported in human carcinomas. As a result, investigators have developed approaches to inhibit the effects of EGFR activation, with the aim of blocking tumor growth and invasion. A number of agents targeting EGFR, including specific antibodies directed against its ligand-binding domain and small molecules inhibiting its tyrosine kinase activity are either in clinical trials or are already approved for clinical treatment.
Journal of Medicinal Chemistry, 1999
A series of 6-and 7-acrylamide derivatives of the 4-(phenylamino)quinazoline and-pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors were prepared from the corresponding amino compounds by reaction with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only the parent quinazoline 7-acrylamide, were irreversible inhibitors of the isolated enzyme, confirming that the former are better-positioned, when bound to the enzyme, to react with the critical cysteine-773. Quinazoline, pyrido[3,4-d]pyrimidine, and pyrido[3,2-d]pyrimidine 6-acrylamides were all irreversible inhibitors and showed similar high potencies in the enzyme assay (likely due to titration of the available enzyme). However the pyrido[3,2-d]pyrimidine analogues were 2-6-fold less potent than the others in a cellular autophosphorylation assay for EGFR in A431 cells. The quinazolines were generally less potent overall toward inhibition of heregulinstimulated autophosphorylation of erbB2 (in MDA-MB-453-cells), whereas the pyridopyrimidines were equipotent. Selected compounds were evaluated in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts. The compounds showed better activity when given orally than intraperitoneally. All showed significant tumor growth inhibition (stasis) over a dose range. The poor aqueous solubility of the compounds was a drawback, requiring formulation as fine particulate emulsions.
Research in Pharmaceutical Sciences
Quinazoline derivatives are potent inhibitors of human epidermal growth factor receptor (EGFR) as anticancer agents. In this study, the cytotoxic effects of a new series of synthesized quinazoline derivatives were evaluated using MTT assay against MCF-7 and HT-29 cell lines. Using molecular docking, the binding modes of all compounds were analyzed at the binding site of EGFR. Based on the results, the compounds L1, L2, L4, L5, L6, L7, L10, L15, and L18 may be promising EGFR inhibitors based on docking score and hydrogen bonds. Consistent with the experimental data, Met769 is recognized as a key residue in the binding of potential inhibitors. According to the MTT cytotoxicity assays, Lipinski's rule of five (RO5), absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and docking studies, three compounds L4, L15, and L10 with IC 50 values of 80, 60, and 1 µM against the MCF-7 were selected for further comparative assessments. The dynamics of free EGFR, and selected ligand-EGFR complexes were investigated using molecular dynamics (MD) simulation studies. The results indicated that the three compounds bound to EGFR active site in a stable manner during the simulation through the formation of new hydrogen bonds with Phe699, Leu694, Gly700, Lys721, Met769, Arg817, and Asp831 with the superiority of compound L15. These features can promote future drug candidate designing to produce better derivatives in the search for the anticancer agents.
Bioorganic & medicinal …, 2003
Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 100 anilinoquinazolines, inhibiting epidermal growth factor receptor (EGFR) kinase. The studies included molecular field analysis (MFA) and receptor surface analysis (RSA). The cross-validated r 2 (r 2 cv ) values are 0.81 and 0.79 for MFA and RSA, respectively. The predictive ability of these models was validated by 28 test set molecules. The results of the best QSAR model were further compared with structure-based investigations using docking studies with the crystal structure of EGFR kinase domain. The results helped to understand the nature of substituents at the 6-and 7-positions, thereby providing new guidelines for the design of novel inhibitors. #
Cancer research, 2001
The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. The best characterized of these proteins are the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecules that are dual inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 microM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per day. In addi...