- Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase
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Irreversible HER/erbB inhibitors selectively inhibit HER-family kinases by targeting a unique cysteine residue located within the ATP-binding pocket. Sequence alignment reveals that this rare cysteine is also present in ten other protein kinases including all five Tec-family members. We demonstrate that the Tec-family kinase Bmx is potently inhibited by irreversible modification at Cys496 by clinical stage EGFR inhibitors such as CI-1033. This cross-reactivity may have significant clinical implications.
- Hur, Wooyoung,Velentza, Anastasia,Kim, Sungjoon,Flatauer, Laura,Jiang, Xinnong,Valente, David,Mason, Daniel E.,Suzuki, Melissa,Larson, Brad,Zhang, Jianming,Zagorska, Anna,DiDonato, Michael,Nagle, Advait,Warmuth, Markus,Balk, Steven P.,Peters, Eric C.,Gray, Nathanael S.
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supporting information; experimental part
p. 5916 - 5919
(2009/06/25)
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- PREVENTIVES AND/OR REMEDIES FOR SUBJECTS WITH THE EXPRESSION OR ACTIVATION OF HER2 AND/OR EGFR
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A Her2 and/or EGFR inhibitor to be administered to a subject determined to show overexpression or activation of Her2 and/or EGFR as a result of a diagnosis of the subject for the expression or activity of Her2 and/or EGFR based on a test for detecting the expression or activity of Her2 and/or EGFR, and a pharmaceutical composition containing the inhibitor.
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Page/Page column 9
(2008/06/13)
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- Preparation of substituted quinazolines
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Methods and materials for preparing irreversible inhibitors of tyrosine kinases of general Formula 1 are disclosed. Such inhibitors, which include N-[4-(3-chloro-4-floro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, are useful for
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- Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4- (phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions
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4-Anilinoquinazoline- and 4-anilinopyrido[3,2-d]pyrimidine-6-acrylamides substituted with solubilizing 7-alkylamine or 7-alkoxyamine side chains were prepared by reaction of the corresponding 6-amines with acrylic acid or acrylic acid anhydrides. In the pyrido[3,2-d]pyrimidine series, the intermediate 6-amino-7-alkylamines were prepared from 7-bromo-6- fluoropyrido[3,2-d]pyrimidine via Stille coupling with the appropriate stannane under palladium-(0) catalysis. This proved a versatile method for the introduction of cationic solubilizing side chains. The compounds were evaluated for their inhibition of phosphorylation of the isolated EGFR enzyme and for inhibition of EGF-stimulated autophosphorylation of EGFR in A431 cells and of heregulin-stimulated autophosphorylation of erbB2 in MDA-MB 453 cells. Quinazoline analogues with 7-alkoxyamine solubilizing groups were potent irreversible inhibitors of the isolated EGFR enzyme, with IC50([app]) values from 2 to 4 nM, and potently inhibited both EGFR and erbB2 autophosphorylation in cells. 7-Alkylamino- and 7- alkoxyaminopyrido[3,2-d]pyrimidines were also irreversible inhibitors with equal or superior potency against the isolated enzyme but were less effective in the cellular autophosphorylation assays. Both quinazoline- and pyrido[3,2- d]pyrimidine-6-acrylamides bound at the ATP site alkylating cysteine 773, as shown by electrospray ionization mass spectrometry, and had similar rates of absorptive and secretory transport in Caco-2 cells. A comparison of two 7- propoxymorpholide analogues showed that the pyrido[3,2-d]pyrimidine-6- acrylamide had greater amide instability and higher acrylamide reactivity, being converted to glutathione adducts in cells more rapidly than the corresponding quinazoline. This difference may contribute to the observed lower cellular potency of the pyrido[3,2-d]pyrimidine-6-acrylamides. Selected compounds showed high in vivo activity against A431 xenografts on oral dosing, with the quinazolines being superior to the pyrido[3,2-d]pyrimidines. Overall, the quinazolines proved superior to previous analogues in terms of aqueous solubility, potency, and in vivo antitumor activity, and one example (CI 1033) has been selected for clinical evaluation.
- Smaill, Jeff B.,Rewcastle, Gordon W.,Loo, Joseph A.,Greis, Kenneth D.,Chan, O. Helen,Reyner, Eric L.,Lipka, Elke,Showalter, H. D. Hollis,Vincent, Patrick W.,Elliott, William L.,Denny, William A.
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p. 1380 - 1397
(2007/10/03)
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