Discovery and Biological Evaluation of Potent Dual ErbB-2/EGFR Tyrosine Kinase Inhibitors: 6-Thiazolylquinazolines

Gaul, Micheal D.; Guo, Yu; Affleck, Karen; Cockerill, G. Stuart; Gilmer, Tona M.; Griffin, Robert J.; Guntrip, Stephen B.; Keith, Barry R.; Knight, Wilson B.; Mullin, Robert J.; Murray, Doris M.; Rusnak, David W.; Smith, Kathryn J.; Tadepalli, Sarva M.; Wood, Edgar R.; Lackey, Karen

doi:10.1016/s0960-894x(02)01047-8

Cited by 53 publications

(31 citation statements)

References 6 publications

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“…To test their functional involvement, we used an inhibitor-based approach, by using specific inhibitors for EGF-R/ErbB2 (GW-583340), 35 the c-MET receptor tyrosine kinase (PHA-665752), 36 and the TGF-␤ type I receptor (LY-364947). 37 All of these kinase inhibitors were administered at a relatively low concentration (0.1 mol/L) to avoid possible cytotoxicity.…”

Section: Cav-1 (P132l): Involvement Of Egf Hgf and Tgf-␤ Signaling mentioning

confidence: 99%

Caveolin-1 (P132L), a Common Breast Cancer Mutation, Confers Mammary Cell Invasiveness and Defines a Novel Stem Cell/Metastasis-Associated Gene Signature

Bonuccelli

Casimiro

Sotgia

et al. 2009

The American Journal of Pathology

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Here we used the Met-1 cell line in an orthotopic transplantation model in FVB/N mice to dissect the role of the Cav-1(P132L) mutation in human breast cancer. Identical experiments were performed in parallel with wild-type Cav-1. Cav-1(P132L) up-regulated the expression of estrogen receptor-␣ as predicted, because only estrogen receptor-␣-positive patients have been shown to harbor Cav-1(P132L) mutations. In the context of primary tumor formation, Cav-1(P132L) behaved as a loss-of-function mutation, lacking any tumor suppressor activity. In contrast, Cav-1(P132L) caused significant increases in cell migration, invasion, and experimental metastasis, consistent with a gain-of-function mutation. To identify possible molecular mechanism(s) underlying this invasive gain-offunction activity, we performed unbiased gene expression profiling. From this analysis, we show that the Cav-1(P132L) expression signature contains numerous genes that have been previously associated with cell migration, invasion, and metastasis. These include i) secreted growth factors and extracellular matrix proteins (Cyr61, Plf, Pthlh, Serpinb5, Tnc, and Wnt10a), ii) proteases that generate EGF and HGF (Adamts1 and St14), and iii) tyrosine kinase substrates and integrin signaling/adapter proteins (Akap13, Cdcp1, Ddef1, Eps15, Foxf1a, Gab2, Hs2st1, and Itgb4). We and others have shown that the caveolin-1 (Cav-1) gene is commonly mutated in human breast cancers.

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Section: Cav-1 (P132l): Involvement Of Egf Hgf and Tgf-␤ Signaling mentioning

confidence: 99%

Caveolin-1 (P132L), a Common Breast Cancer Mutation, Confers Mammary Cell Invasiveness and Defines a Novel Stem Cell/Metastasis-Associated Gene Signature

Bonuccelli

Casimiro

Sotgia

et al. 2009

The American Journal of Pathology

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“…Interestingly, several other groups [13][14][15] have independently discovered, for quinazoline-based inhibitors, that large lipophilic substituents lead to improved HER-2 activity and, in some cases, improved dual HER-2/EGFR activity. 16,17 Here, we describe the synthesis and SAR of a series of 6,7-disubstituted 4-(arylamino)quinoline-3-carbonitriles modified with a variety of lipophilic substituents on the arylamino ring. Compared to our EGFR kinase inhibitor 86, several of these compounds, as exemplified by 25o (Figure 1), show improved activity toward HER-2 kinase while retaining good potency for EGFR kinase.…”

Section: Introductionmentioning

confidence: 99%

Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as Orally Active, Irreversible Inhibitors of Human Epidermal Growth Factor Receptor-2 Kinase Activity

et al. 2005

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A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermal growth factor receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells compared to our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare these compounds. They were prepared mostly by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developed to prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved a safer cyclization step. We show that attaching a large lipophilic group at the para position of the 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also show the importance of a basic dialkylamino group at the end of the Michael acceptor for activity, due to intramolecular catalysis of the Michael addition. This, along with improved water solubility, resulted in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. Binding studies of one compound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474 cells. Furthermore, it demonstrated excellent oral activity, especially in HER-2 overexpressing xenografts. Compound 25o (HKI-272) was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

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“…Although early examples of HER1 kinase inhibitors had only weak affinity for HER2, extensive sequence homology (83% identity) between the two kinase domains suggests that it would be feasible to identify compounds that inhibit both receptors with comparable potency. Recently, quinazoline and pyrrolotriazine analogues that are dual inhibitors of HER1 and HER2 kinases have been identified (27,28). Here we describe the properties of a novel pan-HER kinase inhibitor with broad spectrum antitumor activity, which has advanced into clinical testing.…”

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confidence: 99%

Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer Signaling

Wong¹,

Lee²,

Yu³

et al. 2006

Clinical Cancer Research

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Purpose: The studies described here are intended to characterize the ability of BMS-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (HER) kinase family, to modulate signaling and growth of tumor cells that depend on HER1and/or HER2. Experimental Design: The potency and selectivity of BMS-599626 were assessed in biochemical assays using recombinant protein kinases, as well as in cell proliferation assays using tumor cell lines with varying degrees of dependence on HER1 or HER2 signaling. Modulation of receptor signaling was determined in cell assays by Western blot analyses of receptor autophosphorylation and downstream signaling. The ability of BMS-599626 to inhibit receptor heterodimer signaling in tumor cells was studied by receptor coimmunoprecipitation. Antitumor activity of BMS-599626 was evaluated using a number of different xenograft models that represent a spectrum of human tumors with HER1or HER2 overexpression. Results: BMS-599626 inhibited HER1and HER2 with IC 50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC 50 in the range of 0.24 to 1 Amol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity. Conclusions: BMS-599626 is a highly selective and potent inhibitor of HER1and HER2 kinases and inhibits tumor cell proliferation through modulation of receptor signaling. BMS-599626 inhibits HER1/HER2 receptor heterodimerization and provides an additional mechanism of inhibiting tumors in which receptor coexpression and heterodimerization play a major role in driving tumor growth.The preclinical data support the advancement of BMS-599626 into clinical development for the treatment of cancer.

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Discovery and Biological Evaluation of Potent Dual ErbB-2/EGFR Tyrosine Kinase Inhibitors: 6-Thiazolylquinazolines

Cited by 53 publications

References 6 publications

Caveolin-1 (P132L), a Common Breast Cancer Mutation, Confers Mammary Cell Invasiveness and Defines a Novel Stem Cell/Metastasis-Associated Gene Signature

Caveolin-1 (P132L), a Common Breast Cancer Mutation, Confers Mammary Cell Invasiveness and Defines a Novel Stem Cell/Metastasis-Associated Gene Signature

Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as Orally Active, Irreversible Inhibitors of Human Epidermal Growth Factor Receptor-2 Kinase Activity

Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer Signaling

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