- Synthesis and biological evaluation of irreversible EGFR tyrosine kinase inhibitors containing pyrido[3,4-d]pyrimidine scaffold
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In the present study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-TKIs to overcome acquired EGFR-T790M resistance. The most promising compound 25h inhibited HCC827 and H1975 cells growth with the IC50 values of 0.025 μM and 0.49 μM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFRL858R (IC50 = 1.7 nM) and EGFRL858R/T790M (IC50 = 23.3 nM). 25h could suppress EGFR phosphorylation in HCC827 and H1975 cell lines and significantly induce the apoptosis of HCC827 cells. Additionally, compound 25h could remarkably inhibit cancer growth in established HCC827 xenograft mouse model at 50 mg/kg in vivo. These results indicated that the 2,4-disubstituted 6-(5-substituted pyridin-2-amino)pyrido[3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents.
- Zhang, Hao,Wang, Jin,Zhao, Hong-Yi,Yang, Xue-Yan,Lei, Hao,Xin, Minhang,Cao, Yong-Xiao,Zhang, San-Qi
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- Discovery of Pyridopyrimidinones as Potent and Orally Active Dual Inhibitors of PI3K/mTOR
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The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cell assays, and good pharmacokinetic profile. Furthermore, compound 31 demonstrated in vivo efficacy in a PC-3M tumor xenograft model.
- Yu, Tao,Li, Ning,Wu, Chengde,Guan, Amy,Li, Yi,Peng, Zhengang,He, Miao,Li, Jie,Gong, Zhen,Huang, Lei,Gao, Bo,Hao, Dongling,Sun, Jikui,Pan, Yan,Shen, Liang,Chan, Chichung,Lu, Xiulian,Yuan, Hongyu,Li, Yongguo,Li, Jian,Chen, Shuhui
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p. 256 - 261
(2018/03/21)
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- HETEROCYCLIC COMPOUNDS USEFUL AS PDK1 INHIBITORS
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The present invention provides compounds useful as inhibitors of PDK1. The present invention also provides compositions thereof, and methods of treating PDK1-mediated diseases.
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- Discovery of selective 4-amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization
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Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.
- Crawford, Terry D.,Ndubaku, Chudi O.,Chen, Huifen,Boggs, Jason W.,Bravo, Brandon J.,Delatorre, Kelly,Giannetti, Anthony M.,Gould, Stephen E.,Harris, Seth F.,Magnuson, Steven R.,McNamara, Erin,Murray, Lesley J.,Nonomiya, Jim,Sambrone, Amy,Schmidt, Stephen,Smyczek, Tanya,Stanley, Mark,Vitorino, Philip,Wang, Lan,West, Kristina,Wu, Ping,Ye, Weilan
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p. 3484 - 3493
(2014/05/20)
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- PYRIMIDO [5,4-D] PYRIMIDINE DERIVATIVES FOR THE INHIBITION OF TYROSINE KINASES
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The present invention encompasses compounds of general formula (1), wherein the groups R1 to R4, X1, X2, X3, X4, X5, Q, L1 and L2 are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, as well as pharmaceutical preparations and formulations of these compounds.
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Page/Page column 35
(2010/09/17)
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- Anilinoquinazaolines as protein tyrosine kianse inhibitors
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Heteroaromatic compounds are described, methods for their preparation, pharmaceutical compositions containing them, methods of use, and their use in medicines. In particular, the invention relates to quinazoline and pyridopyrimidine derivatives which exhibit protein tyrosine kinase inhibition.
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Page/Page column 45
(2008/06/13)
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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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- Tyrosine kinase inhibitors. 10. Isomeric 4-[(3-bromophenyl)amino]pyrido[d]-pyrimidines are potent ATP binding site inhibitors of the tyrosine kinase function of the epidermal growth factor receptor
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Following the discovery of the very high inhibitory ability of the 4-[(3-bromophenyl)amino]-quinazolines against the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) (e.g., 3, IC50 0.029 nM), four series of related pyrido[d]pyrimidines bearing electron-donating groups at the 6- or 7-positions have been synthesized and evaluated. The compounds were prepared by nucleophilic substitution of the corresponding 6- and 7-fluoro analogues. While members of all series showed potent inhibitory activity against isolated EGFR, there were important differences between the different isomeric pyrido[d]pyrimidines and the parent quinazolines. Overall, the [3,4-d] and [4,3-d] series were the most potent, followed by the [3,2-d] compounds, with the [2,3-d] analogues being least active. Whereas in the parent quinazoline series the addition of steric bulk to a 6- or 7-NH2 substituent (i.e., NHMe and NMe2 groups) dramatically decreased potency, no such trend was discernable in the [3,2-d] series. Furthermore, in the 7-substituted pyrido[4,3-d]- and 6-substituted pyrido[3,4-d]pyrimidine series, and to a limited extent in the 7-substituted pyrido[2,3-d] series, such substitution increased potency dramatically, to the extent that the 7-(methylamino)pyrido[4,3-d]pyrimidine (5f) (IC50 0.13 nM) and 6-(methylamino)pyrido[3,4-d]pyrimidine (7f) (IC50 0.008 nM) constitute important new leads. Selected compounds were evaluated for their ability to inhibit EGFR autophosphorylation in A431 cells, and a positive quantitative correlation was found between this activity and inhibitory activity against the isolated enzyme.
- Rewcastle, Gordon W.,Palmer, Brian D.,Thompson, Andrew M.,Bridges, Alexander J.,Cody, Donna R.,Zhou, Hairong,Fry, David W.,McMichael, Amy,Denny, William A.
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p. 1823 - 1835
(2007/10/03)
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