2. Academic Validation
  3. Discovery of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent inhibitors of rearranged during transfection (RET) and RET solvent-front mutants for overcoming selpercatinib resistance

Discovery of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent inhibitors of rearranged during transfection (RET) and RET solvent-front mutants for overcoming selpercatinib resistance

  • Eur J Med Chem. 2024 Dec 5:279:116891. doi: 10.1016/j.ejmech.2024.116891.
Junbo Wu 1,  Hanxuan Mo 2,  Zhigang An 2,  Zishu Tang 2,  Xinyu Deng 2,  Huifang Zhou 1,  Yi Gong 3,  Chenggong Zheng 4,  Linsheng Zhuo 5,  Shuguang Tan 6
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, Affiliated Hengyang Hospital of Hunan Normal University & Hengyang Central Hospital, Hengyang, 421001, Hunan, China.
  • 2 Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 3 National Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, China.
  • 4 Pulmonary Hospital, Changsha Central Hospital, Changsha, Hunan, 410004, China.
  • 5 Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: lszhuo@usc.edu.cn.
  • 6 Department of Colorectal Surgery, Affiliated Hengyang Hospital of Hunan Normal University & Hengyang Central Hospital, Hengyang, 421001, Hunan, China. Electronic address: 308805086@qq.com.
PMID: 39316846 DOI: 10.1016/j.ejmech.2024.116891
Abstract

Rearranged during transfection kinase (RET) inhibition has been considered a promising therapeutic approach for treatment of a variety of cancers. However, the clinical therapeutic benefits of the second-generation RET Inhibitor selpercatinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RETG810 R/S/C). Herein, we report a class of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent RET and RET solvent-front mutant inhibitors for overcoming selpercatinib resistance. The representative compound 20p exhibited excellent in vitro inhibitory activities against solvent-front mutations (RETG810R, RETG810S, and RETG810C) with low nanomolar range (IC50 of 5.7-8.3 nM), which was 15-29-fold more potent than selpercatinib (IC50 of 95.3-244.1 nM). Additionally, 20p exhibited acceptable pharmacokinetic properties with oral bioavailability of 30.4 %. Importantly, 20p exhibited highly impressive antitumor potency in both a Ba/F3-KIF5B-RETWT-derived xenograft mouse model and a selpercatinib-resistant Ba/F3-KIF5B-RETG810R-positive mutant xenograft mouse model. Overall, 20p represents a novel and promising drug lead for overcoming RET solvent-front mutation-based resistance to selpercatinib.

Keywords

1,6-Naphthyridine; RET kinase inhibitor; Selpercatinib resistance; Solvent-front mutation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168105
    RET抑制剂
    RET
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