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SHP2 Inhibition Reveals Compensatory PI3K-AKT Activation in KRAS-Driven Pancreatic Cancer: Discovery of SDUY104 and
Chengchun Zhu1,2, Chen Wang3, Yijie Zhu1,2
1Department 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.
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.
Insights
Researchers developed SDUY104, a potent SHP2 inhibitor, to combat KRAS-mutated pancreatic cancer. This new drug halts cancer cell growth and offers a promising strategy when combined with other targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Pancreatic cancer is a deadly disease with frequent KRAS mutations.
- SHP2 inhibitors are a potential therapeutic strategy for KRAS-driven cancers.
Purpose of the Study:
- To develop novel SHP2 allosteric inhibitors.
- To evaluate the efficacy of SDUY104 in KRAS-driven pancreatic cancer models.
- To investigate resistance mechanisms and combination strategies.
Main Methods:
- Lead optimization of furanyl amide-based compounds.
- In vitro enzymatic assays and cell proliferation studies.
- Western blotting for signaling pathway analysis.
- In vivo xenograft studies in mice.
Main Results:
- SDUY104 demonstrated potent SHP2 inhibition and reduced pancreatic cancer cell proliferation.
- SDUY104 induced cell-cycle arrest and apoptosis.
- Combination therapy with ERK or PI3K inhibitors showed synergistic effects.
- SDUY104 plus BKM-120 significantly inhibited tumor growth in vivo.
Conclusions:
- SDUY104 is a potent SHP2 allosteric inhibitor with therapeutic potential for pancreatic cancer.
- Compensatory PI3K-AKT activation is a resistance mechanism to SHP2 inhibition.
- Combination strategies targeting MAPK and PI3K pathways show promise for pancreatic cancer treatment.
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