2. Academic Validation
  3. SHP2 Inhibition Reveals Compensatory PI3K-AKT Activation in KRAS-Driven Pancreatic Cancer: Discovery of SDUY104 and Rational Approaches for Combination Therapy

SHP2 Inhibition Reveals Compensatory PI3K-AKT Activation in KRAS-Driven Pancreatic Cancer: Discovery of SDUY104 and Rational Approaches for Combination Therapy

  • J Med Chem. 2026 Jun 25;69(12):14774-14803. doi: 10.1021/acs.jmedchem.6c00836.
Chengchun Zhu 1 2,  Chen Wang 3,  Yijie Zhu 1 2,  Zongrui Yu 1 2,  Yang Lin 1 2 4,  Yang Zhang 1 2 5,  Yaran Jin 1 2 5,  Naining Zhang 1 2,  Xiaoyu Liu 6,  Xiaohan Ye 1 2,  Kai Chen 6,  Ruirong Tan 7,  Jinbo Yue 8,  Zhiyi Yu 1 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.
  • 2 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
  • 3 Shandong University Cancer Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250117, P.R. China.
  • 4 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China.
  • 5 College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China.
  • 6 Center for New Drug Evaluation, Shandong Academy of Pharmaceutical Sciences, Jinan, Shandong 250000, P.R. China.
  • 7 Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Chengdu, Sichuan 610041, P.R. China.
  • 8 Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China.
PMID: 42261691 DOI: 10.1021/acs.jmedchem.6c00836
Abstract

Pancreatic Cancer remains one of the most lethal malignancies with numerous patients harboring KRAS mutations. Herein, we developed a series of furanyl amide-based SHP2 allosteric inhibitors through optimization of our in-house lead compound SDUY038. Among them, SDUY104 exhibited the most potent enzymatic inhibitory activity and significantly impaired the proliferation of KRAS-driven pancreatic Cancer cells by inducing cell-cycle arrest and Apoptosis. Mechanistic studies revealed that SDUY104 suppressed MAPK signaling while triggering compensatory PI3K-AKT activation. Combining SDUY104 with an ERK Inhibitor Ulixertinib produced synergistic antiproliferative activity via enhanced MAPK suppression. Likewise, coadministrating SDUY104 with a PI3K Inhibitor BKM-120 improved antiproliferative efficacy by reversing PI3K-AKT feedback activation. In a PANC-1 xenograft model, combination of SDUY104 with BKM-120 exhibited superior antitumor activity compared to either monotherapy. Collectively, this study identifies a potent SHP2 allosteric inhibitor and delineates a critical compensatory signaling mechanism underlying resistance to SHP2-targeted therapy, providing proof-of-concept support for pancreatic Cancer treatment.

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