1245555-80-9Relevant academic research and scientific papers
Potential applications of clickable probes in EGFR activity visualization and prediction of EGFR-TKI therapy response for NSCLC patients
Deng, Hui,Lei, Qian,Shang, Weidong,Li, Ying,Bi, Liyun,Yang, Na,Yu, Zhiyi,Li, Weimin
, (2022/01/13)
The epithelial growth factor receptor (EGFR) is abnormally overexpressed on the cell surface of cancer cells and is strongly associated with cancer cell proliferation, migration, differentiation, apoptosis, and angiogenesis. Tools enabling the visualization of EGFR in a structure-function approach are highly desirable to predict EGFR mutations and guide EGFR tyrosine kinase inhibitor (TKI) treatment making. Here, we describe the design, synthesis, and application of new, potent and selective clickable probes 13 (HX03), 20 (HX04) and 24 (HX05) by introducing an alkyne ligation handle to visualize EGFR activity in living cancer cells and tissue slices. These clickable probes are versatile chemical tools based on the key pharmacophore (4-anilinoquinazoline) of EGFR-TKIs (e.g., canertinib, dacomitinib and afatinib) and are able to irreversibly target the kinase domain of EGFR. Among them, 13 exhibits the highest reactivity towards EGFR kinase, particularly to EGFR kinase with primary mutations. Using activity-based protein profiling strategy, 13 showed high sensitivity and selectivity in labeling of endogenous EGFR in a native cellular context. Moreover, 13 was applied to visualize EGFR mutant activity in tumour tissues from non-small-cell lung cancer (NSCLC) xenograft mouse models, and patients with NSCLC for the prediction of EGFR-TKI sensitivity. These results demonstrate that strategically designed EGFR-TKI-based probes allow discriminating EGFR mutations in human tissues and hold promise as useful diagnostic tools in predicting EGFR-TKI therapy response.
EGFR PROTEOLYSIS TARGETING CHIMERIC MOLECULES AND ASSOCIATED METHODS OF USE
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, (2018/07/29)
The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
NOVEL FLUORINATED QUINAZOLINE DERIVATIVES AS EGFR INHIBITORS
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Paragraph 00203, (2017/08/01)
A novel class of fluorinated derivatives of Formula (I) have been prepared and found to be useful in the treatment of cancers and other EGFR related disorders. (I)
Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family
Smaill, Jeff B.,Gonzales, Andrea J.,Spicer, Julie A.,Lee, Helen,Reed, Jessica E.,Sexton, Karen,Althaus, Irene W.,Zhu, Tong,Black, Shannon L.,Blaser, Adrian,Denny, William A.,Ellis, Paul A.,Fakhoury, Stephen,Harvey, Patricia J.,Hook, Ken,McCarthy, Florence O. J.,Palmer, Brian D.,Rivault, Freddy,Schlosser, Kevin,Ellis, Teresa,Thompson, Andrew M.,Trachet, Erin,Winters, R. Thomas,Tecle, Haile,Bridges, Alexander
, p. 8103 - 8124 (2016/10/06)
Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors
Zhang, Long,Yang, Yingying,Zhou, Haojie,Zheng, Qingmei,Li, Yuhao,Zheng, Shansong,Zhao, Shuyong,Chen, Dong,Fan, Chuanwen
, p. 445 - 463 (2015/09/01)
We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.
QUINAZOLINE DERIVATIVES, COMPOSITIONS THEREOF, AND USE AS PHARMACEUTICALS
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Page/Page column 25-26, (2015/02/02)
Disclosed herein are protein kinase inhibitors, more particularly novel quinazoline derivatives and pharmaceutical compositions thereof,and method of use thereof.
QUINAZOLINE DERIVATIVE AS TYROSINE-KINASE INHIBITOR, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF
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, (2014/06/24)
The invention relates to a quinazoline derivative represented by the general formula (I), a pharmaceutical acceptable salt and a stereoisomer thereof as tyrosine kinase inhibitor, wherein R1, R2, R3, R3′, R
AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE THEREOF
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, (2014/11/13)
Provided herein are aminoquinazoline compounds, salts and uses thereof. The compounds have Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug ther
PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY
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Page/Page column 34; 43, (2010/10/03)
The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R1 is a group of the formula —(CH2)nTr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and —(CH2)nTr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R2, R3 and R4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R2)(R3)(R4)N, or two of R2, R3, and R4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R2, R3 and R4 may be absent and two of R2, R3 and R4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.
