2. Academic Validation
  3. Discovery of novel covalent agonists for p53 Y220C through synergistic strategy combining covalent binding and scaffold hopping

Discovery of novel covalent agonists for p53 Y220C through synergistic strategy combining covalent binding and scaffold hopping

  • Eur J Med Chem. 2026 Jul 5:311:118801. doi: 10.1016/j.ejmech.2026.118801.
Linquan Li 1,  Jingyi Meng 2,  Fengqian Xu 1,  Kang Wang 1,  Xiaoqian Wang 1,  Xi Gu 1,  Haiwei Shen 3,  Sulin Zhang 4,  Zhili Zuo 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou, 310024, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou, 310024, China. Electronic address: shenhw@ucas.ac.cn.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou, 310024, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: slzhang@simm.ac.cn.
  • 5 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou, 310024, China. Electronic address: zlzuo@ucas.ac.cn.
PMID: 41934688 DOI: 10.1016/j.ejmech.2026.118801
Abstract

The Y220C mutation represents one of the most frequent mutational variants in p53. This mutant impairs p53-mediated tumor suppression and heightens oncogenic risk. Consequently, activating the antitumor function of p53 mutants emerges as a promising therapeutic strategy for diverse malignancies. Herein, we report a strategic concept targeting the shallow neomorphic pocket created by the p53 Y220C mutant with covalent small molecules. Utilizing scaffold hopping, we identified the privileged pyrrolopyrimidine scaffold and subsequently designed high-potency compounds through covalent warhead replacement and systematic structural optimization. The protein thermal shift assay confirmed enhanced thermal stabilization of p53 Y220C. Several compounds restored its DNA-binding capacity. Among them, LLQ-45 showed selective activity against p53 Y220C-mutant tumor cells, inhibiting their proliferation and markedly upregulating CDKN1A expression in a dose-dependent manner. These results demonstrate that LLQ-45 activates the antitumor function of p53 Y220C via covalent modification, thereby suppressing tumor cell growth. This study provides a framework for targeting neomorphic pockets and advances targeted Cancer therapies.

Keywords

Activator; Drug design; Structural modification; Synthesis; p53 Y220C.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-182744
    p53 Y220C激动剂
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