Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold

SHP2 plays a critical role in modulating
tumor growth
and PD-1-related
signaling pathway, thereby serving as an attractive antitumor target.
To date, no antitumor drugs targeting SHP2 have been approved, and
hence, the search of SHP2 inhibitors with new chemical scaffolds is
urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor
SDUY038 with a furanyl amide scaffold, demonstrating potent binding
affinity (KD = 0.29 μM), enzymatic
activity (IC50 = 1.2 μM) and similar binding interactions
to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor
activity (IC50 = 7–24 μM) by suppressing pERK
expression. Furthermore, SDUY038 significantly inhibited tumor growth
in both xenograft and organoid models. Additionally, SDUY038 displayed
acceptable bioavailability (F = 14%) and half-life
time (t1/2 = 3.95 h). Conclusively, this
study introduces the furanyl amide scaffold as a novel class of SHP2
allosteric inhibitors, offering promising lead compounds for further
development of new antitumor therapies targeting SHP2.