2. Academic Validation
  3. Design, synthesis, and activity evaluation of selective CDK9 inhibitors containing indazole fragments

Design, synthesis, and activity evaluation of selective CDK9 inhibitors containing indazole fragments

  • Bioorg Chem. 2025 Nov:166:109083. doi: 10.1016/j.bioorg.2025.109083.
Xizhe Sun 1,  Houlin Peng 2,  Xiayu Li 1,  Li Tang 1,  Xianzong Ma 1,  Ye Zhong 3,  Huali Yang 4,  Yang Liu 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Department of Pharmaceutics, Shenyang Pharmaceutical University, 110016 Shenyang, China.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: zy_mc666@sina.com.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: yanghl@syphu.edu.cn.
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: y.liu@syphu.edu.cn.
PMID: 41086724 DOI: 10.1016/j.bioorg.2025.109083
Abstract

Targeting the inhibition of CDK9 represents a promising therapeutic strategy for colorectal Cancer. This study designed and synthesized two series (A and B) of 28 unreported compounds based on rational structural modification of the lead compound AZD5438. Among them, compound B11 exhibited comparable in vitro antiproliferative activity to AZD5438 against three colorectal Cancer cell lines (HCT116, RKO, and HT-29), along with superior selectivity for CDK9 inhibition, displaying an IC50 of 7.13 nM. The selective binding mode of B11 toward CDK9 was analyzed using molecular dynamics simulations and MM/GBSA calculations. Mechanistic studies demonstrated that B11 induces Apoptosis in HCT116 cells by elevating intracellular ROS levels through suppression of anti-apoptotic protein expression and activating the Caspase-3 pathway. In conclusion, compound B11 may serve as a novel selective CDK9 Inhibitor worthy of further development for colorectal Cancer treatment.

Keywords

Apoptosis assays; MM/GBSA; Molecular dynamics simulation; Selective CDK inhibitors; colorectal cancer.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z