Lead optimization and efficacy evaluation of quinazoline-based BET family inhibitors for potential treatment of cancer and inflammatory diseases

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Yang, Shyh-Ming¹  Yoshioka, Makoto²  Strovel, Jeffrey W.²  Urban, Daniel J.¹  Hu, Xin¹  Hall, Matthew D.¹  Jadhav, Ajit¹  Maloney, David J.¹ 

[1] NIH, Natl Ctr Advancing Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA

[2] ConverGene LLC, 3093 Beverly Lane,Unit C, Cambridge, MD 21613 USA

关键词: BET inhibitor;    BRD4;    Bromodomain;    Quinazoline;    Cancer;    Inflammatory diseases;   

DOI  :  10.1016/j.bmcl.2019.03.014

来源: Elsevier

【 摘 要 】

Extensive optimization of quinazoline-based lead 8 is described. The structure-activity relationship studies indicate the S-configuration is preferred for the phenylmorpholine substitution. Together with incorporation of a (2-hydroxyl-2-methylpropyl)pyrazole moiety at the 2-position leads to analogs with comparable potency and marked improvement in the pharmacokinetic profile over our previously reported lead compounds. Further in vivo efficacy studies in Kasumi-1 xenograft mouse model demonstrates that the selected inhibitors are well tolerated and highly efficacious in the inhibition of tumor growth. Additionally, the representative analog 19 also demonstrated significant improvement of arthritis severity in a collagen-induced arthritis (CIA) mouse model. These results indicate potential use of these quinazoline-based BET inhibitors for treatment of cancer and inflammatory diseases. A brief discussion of the co-crystallized structure of 19 with BRD4 (BD1) is also highlighted.

【 授权许可】

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