Discovery of Novel Dual Small-Molecule Inhibitors Targeting SHP2 and NAMPT for Overcoming Resistance to Allosteric SHP2 Inhibition.

Authors

Kaizhen Wang, Yijiao Liu, Zhiyi Zhang, Yingxin Hu, Yuhua Zhong, Sheng Jiang, Xiangyu Zhang, Kuojun Zhang, Tianyu Wang

Published in

Journal of medicinal chemistry. Jun 22, 2026. Epub Jun 22, 2026.

Abstract

Inhibition of the Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) represents a promising therapeutic strategy for cancer. However, resistance to SHP2 inhibition, mediated by multiple mechanisms, has limited the clinical efficacy of SHP2 inhibitor monotherapy. Herein, we identified that nicotinamide phosphoribosyltransferase (NAMPT) inhibition could potentially overcome resistance to SHP2 inhibition in tumor cells. Compound A4 was identified as the most potent dual inhibitor targeting SHP2 and NAMPT, exhibiting high inhibitory activity against both SHP2 and NAMPT. A4 effectively inhibited proliferation in SHP099-insensitive tumor cell lines and reversed programmed cell death ligand 1 (PD-L1)-mediated immunosuppression. Furthermore, A4 displayed significant in vivo antitumor efficacy in an MDA-MB-231 mouse model and strongly promoted in vivo antitumor immunity in a 4T1 mouse model. Our results identified A4 as a promising dual SHP2 and NAMPT inhibitor, providing a novel therapeutic strategy for overcoming resistance to allosteric SHP2 inhibition.

PMID:
42324937
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.