1269232-99-6Relevant academic research and scientific papers
Design, Synthesis, and Biological Evaluation of 1-(Indolizin-3-yl)ethan-1-ones as CBP Bromodomain Inhibitors for the Treatment of Prostate Cancer
Xiang, Qiuping,Wang, Chao,Wu, Tianbang,Zhang, Cheng,Hu, Qingqing,Luo, Guolong,Hu, Jiankang,Zhuang, Xiaoxi,Zou, Lingjiao,Shen, Hui,Wu, Xishan,Zhang, Yan,Kong, Xiangqian,Liu, Jinsong,Xu, Yong
, p. 785 - 810 (2022/01/12)
CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) is a potential target for prostate cancer treatment. Herein, we report the structural optimization of a series of 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led to compound 9g (Y08284), which possesses good liver microsomal stability and pharmacokinetic properties (F = 25.9%). Furthermore, the compound is able to inhibit CBP bromodomain as well as the proliferation, colony formation, and migration of prostate cancer cells. Additionally, the new inhibitor shows promising antitumor efficacy in a 22Rv1 xenograft model (TGI = 88%). This study provides new lead compounds for further development of drugs for the treatment of prostate cancer.
Development of a Potent Brain-Penetrant EGFR Tyrosine Kinase Inhibitor against Malignant Brain Tumors
Tsang, Jonathan E.,Urner, Lorenz M.,Kim, Gyudong,Chow, Kingsley,Baufeld, Lynn,Faull, Kym,Cloughesy, Timothy F.,Clark, Peter M.,Jung, Michael E.,Nathanson, David A.
supporting information, p. 1799 - 1809 (2020/11/09)
The epidermal growth factor receptor (EGFR) is genetically altered in nearly 60% of glioblastoma tumors; however, tyrosine kinase inhibitors (TKIs) against EGFR have failed to show efficacy for patients with these lethal brain tumors. This failure is attributed to the inability of clinically tested EGFR TKIs to cross the blood-brain barrier (BBB) and achieve adequate pharmacological levels to inhibit various oncogenic forms of EGFR that drive glioblastoma. Through SAR analysis, we developed compound 5 (JCN037) from an anilinoquinazoline scaffold by ring fusion of the 6,7-dialkoxy groups to reduce the number of rotatable bonds and polar surface area and by introduction of an ortho-fluorine and meta-bromine on the aniline ring for improved potency and BBB penetration. Relative to the conventional EGFR TKIs erlotinib and lapatinib, JCN037 displayed potent activity against EGFR amplified/mutant patient-derived cell cultures, significant BBB penetration (2:1 brain-to-plasma ratio), and superior efficacy in an EGFR-driven orthotopic glioblastoma xenograft model.
FUSED RING COMPOUNDS
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Paragraph 0566, (2020/03/05)
Provided are fused ring compounds of Formula (I), Formula (II), or Formula (III), as further detailed herein, which are used for the inhibition of Ras proteins, as well as compositions comprising these compounds and methods treatment by their administration.
Compounds and Compositions as Protein Kinase Inhibitors
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, (2011/04/14)
The present invention provides compounds of Formula I or II: wherein R1, R1b, R2, R3, R4, R5, R6 and R7 are defined herein. The compounds of Formula (I) or (II) and pharmaceutical compositions thereof are useful for the treatment of B-Raf-associated diseases.
COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
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Page/Page column 49, (2011/04/14)
The invention provides a novel class of compounds of formula 1, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of B-Raf.
