A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib)

Wood, Edgar R.; Truesdale, Anne T.; McDonald, Octerloney B.; Yuan, Derek; Hassell, Anne M.; Dickerson, Scott H.; Ellis, Byron; Pennisi, Christopher; Horne, Earnest; Lackey, Karen; Alligood, Krystal J.; Rusnak, David W.; Gilmer, Tona M.; Shewchuk, Lisa M.

doi:10.1158/0008-5472.can-04-1168

Cited by 1,003 publications

(431 citation statements)

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“…Other analogs in series B are also less active than their isomeric counterparts in series A, with the exception of the simple acetylene derivative 10, which had similar potency to 6 in the ErbB-2 cellular assay. The x-ray crystal structure of erlotinib and lapatinib bound to EGFR have both been reported (11,12). As described previously, the structure of lapatinib in EGFR revealed that the bulky benzyloxy aniline head group induced a significant conformational shift of the enzyme relative to erlotinib.…”

Section: Enzyme and Cellularmentioning

confidence: 67%

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6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases

Wood

Shewchuk²,

Ellis³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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November 5, 2007; 10.1073͞pnas.0702843104), the authors wish to add a reference to a paper by A. Shukla et al. (35), in which an intrinsic, nonaromatic fluorescence emission with the same excitation and emission characteristics was observed in different protein crystals and aggregates, upon UV-A excitation, and was attributed to the delocalization of peptide electrons by intra-and/or intermolecular hydrogen bond formation, consistent with the intrinsic blue-green fluorescence we report in amyloid-like nanofibrils. The added reference appears below. Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678 -1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.inhibitors ͉ enzyme ͉ irreversible ͉ thiol ͉ alkylation I nhibition of the ErbB family receptor tyrosine kinases (EGFR, ErbB-2) represents a major advance in the treatment of solid tumors, as demonstrated by the promising clinical activity of gefitinib (1), erlotinib (2), and lapatinib (3) (Fig. 1) (1). These drugs are selective, reversible ATP-competitive EGFR (e.g., 1, 2) or dual EGFR/ErbB-2 inhibitors (3), respectively. An alternative approach for targeting this family of enzymes has been through irreversible alkylation of an ErbB family-conserved cysteine residue (Cys-797 in EGFR, Cys-805 in ErbB-2, and Cys-803 in ErbB-4). i This latter approach led to the discovery of the potent, irreversible agents canertinib (4) and pelitinib (5) (Fig. 1) (2, 3). Both compounds 4 and 5 and other irreversible agents are reported to be in phase II clinical trials (4).To identify potent, efficacious EGFR/ErbB-2 inhibitors structurally distinct from lapatinib, a series of 4-anilino thienopyrimidines containing the fluorobenzyl aniline subunit common to 3 was explored. Optimization of this series on enzyme and cellular assays led to the identification of 6-ethynyl-substituted thieno[3,2-d]pyrimidines and thieno [2,3-d]pyrimidines as represented by the...

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Section: Enzyme and Cellularmentioning

confidence: 67%

“…The inhibitor aniline substituent binds in the ''backpocket'' of the enzyme in a manner similar to that of lapatinib in EGFR ( Fig. 3B) (12). Of key significance, the thienopyrimidine inhibitor ErbB-4 structure revealed a covalent bond between the Cys-803 sulfhydryl group and the acetylene terminus of the inhibitor ( Fig.…”

Section: Enzyme and Cellularmentioning

confidence: 93%

6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases

Wood

Shewchuk²,

Ellis³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The recent discovery that mutations in the epidermal growth factor receptor (EGFR) confer sensitivity to EGFR inhibitors in non-small-cell lung cancer patients raises the possibility that acquired resistance to these drugs may occur through an analogous mechanism (20,23). The two most widely studied EGFR inhibitors, gefitinib and erlotinib, are thought to bind EGFR in the active conformation, whereas lapatinib, a third compound in clinical trials, binds EGFR in an inactive-like conformation (24,25). Comparative studies of these compounds may reveal distinct resistance mechanisms and could provide rationale for combination therapy, or for a search for additional, more conformation-tolerant EGFR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance

Burgess

Skaggs²,

Shah³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

291

221

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Structural studies suggest that most point mutations in the BCR-ABL kinase domain cause resistance to the ABL kinase inhibitor imatinib by impairing the flexibility of the kinase domain, restricting its ability to adopt the inactive conformation required for optimal imatinib binding, rather than by directly interfering with drug contact residues. BMS-354825, currently in clinical development for imatinib-resistant chronic myelogenous leukemia, is a dual SRC͞ABL kinase inhibitor that binds ABL in both the active and inactive conformation. To examine the potential role of conformational binding properties in drug resistance, we mapped the mutations in BCR-ABL capable of conferring resistance to BMS-354825. Through saturation mutagenesis, we identified 10 such BCR-ABL mutations, 8 of which occurred at drug contact residues. Some mutants were unique to BMS-354825, whereas others also conferred imatinib resistance. Remarkably, the identity of the amino acid substitution at either of two contact residues differentially affects sensitivity to imatinib or BMS-354825. The combination of imatinib plus BMS-354825 greatly reduced the recovery of drug-resistant clones. Our findings provide further rationale for considering kinase conformation in the design of kinase inhibitors against cancer targets.BMS-354825 ͉ chronic myeloid leukemia ͉ imatinib ͉ mutagenesis

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“…19 Unlike erlotinib and gefitinib, lapatinib (Tykerb/Tyverb) is a dual tyrosine kinase inhibitor that forms relatively selective and unique complexes with both EGFR and HER2. 20 Several clinical trials established lapatinib's activity, together with chemotherapy, in the treatment of patients with HER2-positive advanced breast cancer previously treated with trastuzumab and chemotherapy. 21 Afatinib is the first clinically approved TKI of the second generation of HER/ERBB inhibitors, designed to have more potent inhibition of EGFR and to overcome the EGFR T790M resistance mutation.…”

Section: Targeted Cancer Therapy Directed At the Egfr (Her/ Erbb) Familymentioning

confidence: 99%

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

Gaborit

Lindzen

Yarden

2015

Human Vaccines & Immunotherapeutics

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Cancer progression depends on stepwise accumulation of oncogenic mutations and a select group of growth factors essential for tumor growth, metastasis and angiogenesis. Agents blocking the epidermal growth factor receptor (EGFR, also called HER1 and ERBB1) and the co-receptor called HER2/ERBB2 have been approved over the last decade as anti-cancer drugs. Because the catalytically defective member of the family, HER3/ERBB3, plays critical roles in emergence of resistance of carcinomas to various drugs, current efforts focus on antibodies and other anti-HER3/ERBB3 agents, which we review herein with an emphasis on drug combinations and some unique biochemical features of HER3/ERBB3.

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A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib)

Cited by 1,003 publications

References 28 publications

6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases

6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases

Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

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