2. Academic Validation
  3. Discovery of highly potent and selective KRASG12C degraders by VHL-recruiting PROTACs for the treatment of tumors with KRASG12C-Mutation

Discovery of highly potent and selective KRASG12C degraders by VHL-recruiting PROTACs for the treatment of tumors with KRASG12C-Mutation

  • Eur J Med Chem. 2023 Dec 5:261:115857. doi: 10.1016/j.ejmech.2023.115857.
Ning Yang 1,  Zhiya Fan 2,  Shiyang Sun 1,  Xiaotong Hu 1,  Yaqiu Mao 1,  Changkai Jia 1,  Xu Cai 1,  Tingting Xu 1,  Bingkun Li 1,  Yi Li 1,  Luobing Han 1,  Ting Wei 1,  Xiaohong Qian 2,  Weijie Qin 3,  Pengyun Li 4,  Zhibing Zheng 5,  Song Li 1
Affiliations

Affiliations

  • 1 National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology Institution, Beijing, 100850, China.
  • 2 National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing, 102206, China.
  • 3 National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing, 102206, China. Electronic address: aunp_dna@126.com.
  • 4 National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology Institution, Beijing, 100850, China. Electronic address: bnuhuaxuelpy@163.com.
  • 5 National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology Institution, Beijing, 100850, China. Electronic address: zzbcaptain@aliyun.com.
PMID: 37852032 DOI: 10.1016/j.ejmech.2023.115857
Abstract

Although several covalent KRASG12C inhibitors have made great progress in the treatment of KRASG12C-mutant Cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRASG12C Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRASG12C-dependent Cancer cells growth with nanomolar IC50 and DC50 values, and ＞ 95 % maximum degradation (Dmax). Molecular dynamics (MD) simulation showed that YN14 induced a stable KRASG12C: YN14: VHL ternary complex with low binding free energy (ΔG). Notably, YN14 led to tumor regression with tumor growth inhibition (TGI%) rates more than 100 % in the MIA PaCa-2 xenograft model with well-tolerated dose-schedules. We also found that KRASG12C degradation exhibited advantages in overcoming adaptive KRASG12C feedback resistance over KRASG12C inhibition. Furthermore, combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRASG12C-mutant Cancer cells. Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRASG12C-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination.

Keywords

Adaptive resistance; Cancer therapy; Drug combination; KRAS(G12C); Proteolysis-targeting chimeras (PROTACs).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155356
    KRASG12C降解剂
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