Abstract：
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.
摘要：
SHP2在调节肿瘤生长和PD-1相关信号通路中起关键作用，从而充当有吸引力的抗肿瘤靶标。迄今为止,尚未批准针对SHP2的抗肿瘤药物，因此，迫切需要寻找具有新化学支架的SHP2抑制剂。在这里，我们开发了一种具有呋喃酰胺支架的新型SHP2变构抑制剂SDUY038，表现出有效的结合亲和力（KD=0.29μM），酶活性（IC50=1.2μM）和与SHP099的类似结合相互作用。在细胞层面,SDUY038通过抑制pERK表达表现出泛抗肿瘤活性(IC50=7-24μM)。此外，SDUY038在异种移植和类器官模型中均显着抑制肿瘤生长。此外,SDUY038显示出可接受的生物利用度(F=14%)和半衰期(t1/2=3.95h)。最后，这项研究介绍了呋喃酰胺支架作为一类新型的SHP2变构抑制剂，为进一步开发针对SHP2的新抗肿瘤疗法提供有前途的先导化合物。
