Design, synthesis and biological evaluation of 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives as CDK inhibitors.

Content Provider	Europe PMC
Author	Yang, Bo Quan, Yanni Zhao, Wuli Ji, Yingjie Yang, Xiaotang Li, Jianrui Li, Yi Liu, Xiujun Wang, Ying Li, Yanping
Copyright Year	2023
Abstract	To explore the potential use of CDK inhibitors in pancreatic ductal adenocarcinoma (PDAC) therapy, a series of novel 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives was designed, synthesised, and investigated for inhibition on both CDK kinase activity and cellular proliferation of pancreatic cancer. Most of new sulphonamide-containing derivatives demonstrated strong inhibitory activity on CDK9 and obvious anti-proliferative activity in cell culture. Moreover, two new compounds suppressed cell proliferation of multiple human pancreatic cancer cell lines. The most potent compound 2g inhibited cancer cell proliferation by blocking Rb phosphorylation and induced apoptosis via downregulation of CDK9 downstream proteins Mcl-1 and c-Myc in MIA PaCa-2 cells. CDK9 knockdown experiment suggests its anti-proliferative activity is mainly mediated by CDK9. Additionally, 2g displayed moderate tumour inhibition effect in AsPC-1 derived xenograft mice model. Altogether, this study provided a new start for further optimisation to develop potential CDK inhibitor candidates for PDAC treatment by alone or combination use.
Page Count	15
ISSN	14756366
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume Number	38
PubMed Central reference number	PMC9858427
Issue Number	1
PubMed reference number	36656085
e-ISSN	14756374
DOI	10.1080/14756366.2023.2169282
Language	English
Publisher	Taylor & Francis
Publisher Date	2023-12-01
Access Restriction	Open
Rights License	This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Subject Keyword	Cell cycle-dependent kinase inhibitor 2-((4-sulfamoylphenyl)amino)-pyrrolo[23-d]pyrimidine derivatives pancreatic ductal adenocarcinoma anti-proliferative activity oral pharmacokinetics
Content Type	Text
Resource Type	Article
Subject	Medicine Drug Discovery Pharmacology