- Targeting Her2-insYVMA with Covalent Inhibitors - A Focused Compound Screening and Structure-Based Design Approach
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Mutated or amplified Her2 serves as a driver of non-small cell lung cancer or mediates resistance toward the inhibition of its family member epidermal growth factor receptor with small-molecule inhibitors. To date, small-molecule inhibitors targeting Her2 which can be used in clinical routine are lacking, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds, which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion parameters as well as mass spectrometry experiments and western blot analysis substantiated our approach.
- Lategahn, Jonas,Hardick, Julia,Grabe, Tobias,Niggenaber, Janina,Jeyakumar, Kirujan,Keul, Marina,Tumbrink, Hannah L.,Becker, Christian,Hodson, Luke,Kirschner, Tonia,Kl?vekorn, Philip,Ketzer, Julia,Baumann, Matthias,Terheyden, Susanne,Unger, Anke,Weisner, J?rn,Müller, Matthias P.,Van Otterlo, Willem A. L.,Bauer, Sebastian,Rauh, Daniel
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p. 11725 - 11755
(2020/11/26)
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- Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors
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In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the
- Milik, Sandra N.,Abdel-Aziz, Amal Kamal,Lasheen, Deena S.,Serya, Rabah A.T.,Minucci, Saverio,Abouzid, Khaled A.M.
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p. 316 - 336
(2018/06/14)
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- Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
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A pharmaceutical formulation comprising the compound of formula
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Page/Page column 39; 40
(2015/12/18)
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- NOVEL AMINE DERIVATIVE OR SALT THEREOF
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A novel amine derivative expressed by general formula (1) (in the formula: G1, G2, and G3 are the same or different and represent CH or a nitrogen atom; R1 represents a chlorine atom, an optionally-substituted C3-8 cycloalkyl group, or the like; R2 represents -COOR5 (in the formula, R5 represents a hydrogen atom or a carboxyl protective group), or the like; R3 represents a hydrogen atom, or the like; and R4 represents an optionally-substituted condensed bicyclic hydrocarbon group, an optionally-substituted bicyclic heterocyclic group, or the like), or a salt thereof is useful in procedures such as the treatment or prevention of conditions related to excessive keratinocyte proliferation.
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Paragraph 0454-0455; 0577-0578
(2015/11/11)
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- Synthesis and cytotoxic activity of 2,5-disubstituted pyrimido[5,4-c] quinoline derivatives
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A series of 2,5-disubstituted pyrimido[5,4-c]quinoline derivatives were synthesized and their cytotoxic activity against H460, HT-29 and MDA-MB-231 cell lines was evaluated in vitro. It was found that most of the tested compounds especially compound 17, s
- Zhang, Fan,Zhai, Xin,Chen, Li Juan,Qi, Jian Guo,Cui, Bo,Gu, Yu Cheng,Gong, Ping
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p. 1277 - 1280
(2012/01/06)
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- Synthesis and evaluation of aniline headgroups for alkynyl thienopyrimidine dual EGFR/ErbB-2 kinase inhibitors
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Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced a
- Waterson, Alex G.,Petrov, Kimberly G.,Hornberger, Keith R.,Hubbard, Robert D.,Sammond, Douglas M.,Smith, Stephon C.,Dickson, Hamilton D.,Caferro, Thomas R.,Hinkle, Kevin W.,Stevens, Kirk L.,Dickerson, Scott H.,Rusnak, David W.,Spehar, Glenn M.,Wood, Edgar R.,Griffin, Robert J.,Uehling, David E.
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experimental part
p. 1332 - 1336
(2009/11/30)
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- Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity
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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.
- Tsou, Hwei-Ru,Overbeek-Klumpers, Elsebe G.,Hallett, William A.,Reich, Marvin F.,Floyd, M. Brawner,Johnson, Bernard D.,Michalak, Ronald S.,Nilakantan, Ramaswamy,Discafani, Carolyn,Golas, Jonathan,Rabindran, Sridhar K.,Shen, Ru,Shi, Xiaoqing,Wang, Yu-Fen,Upeslacis, Janis,Wissner, Allan
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p. 1107 - 1131
(2007/10/03)
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- SUBSTITUTED TETRAHYDROBENZOTHIENOPYRIMIDINAMINE COMPOUNDS USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS
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The present invention relates to a compound of Formula (I) and its use in treating hyper-proliferative disorders.
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Page/Page column 117-118
(2010/02/10)
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- Substituted triazinyl acrylamide derivatives and methods of use
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The invention encompasses compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions, uses and methods for prophylaxis and treatment of cancer and polycystic kidney disease.
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- Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and c-erbB-2
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Described herein is the design and synthesis of indazolylaminopyridopyrimidines and quinazolines as inhibitors of the class 1 tyrosine kinase receptor family. Data is presented for N4-(1-benzyl-1H-indazol-5-yl)-N6,N6- dime
- Cockerill, Stuart,Stubberfield, Colin,Stables, Jeremy,Carter, Malcolm,Guntrip, Stephen,Smith, Kathryn,McKeown, Steve,Shaw, Robert,Topley, Peter,Thomsen, Lindy,Affleck, Karen,Jowett, Amanda,Hayes, David,Willson, Malcolm,Woollard, Patrick,Spalding, David
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p. 1401 - 1405
(2007/10/03)
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