2. Academic Validation
  3. Structure-guided expansion strategy unveils potent allosteric SHP2 inhibitors with synergistic efficacy against AML through MCL-1 co-targeting

Structure-guided expansion strategy unveils potent allosteric SHP2 inhibitors with synergistic efficacy against AML through MCL-1 co-targeting

  • Eur J Med Chem. 2025 Nov 15:298:117988. doi: 10.1016/j.ejmech.2025.117988.
Maoqian Zhang 1,  Shuyun Wu 1,  Menghui Liu 1,  Haozhe Li 1,  Luyao Wang 1,  Feimeng Duan 1,  Rui Han 1,  Chenxiao Shan 1,  Zequn Jiang 2,  Junzhuo Liao 3,  Yongmin Zhang 4,  Wei Li 5,  Bo Wang 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 2 School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3 Department of Chemistry, Columbia University, 3000 Broadway, New York, NY, 10027, USA. Electronic address: jl6403@columbia.edu.
  • 4 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 place Jussieu, 75005, Paris, France. Electronic address: yongmin.zhang@upmc.fr.
  • 5 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: liwaii@njucm.edu.cn.
  • 6 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: bwang@njucm.edu.cn.
PMID: 40730062 DOI: 10.1016/j.ejmech.2025.117988
Abstract

SHP2, an oncogenic Phosphatase pivotal in RAS-MAPK, PI3K-AKT, and JAK-STAT signaling, represents a compelling therapeutic target in malignancies driven by its hyperactivation. While allosteric inhibitors like SHP099 have overcome historical challenges of orthosteric agents by stabilizing SHP2's autoinhibited conformation, opportunities remain to enhance potency, selectivity, and clinical utility. Here, we report a structure-guided expansion strategy leveraging detailed profiling of the tunnel-shaped allosteric pocket to design next-generation inhibitors. Systematic optimization of a pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one scaffold yielded compounds B1 and B8, which exhibit nanomolar enzymatic inhibition (IC50 = 39 and 15 nM), acceptable pharmacokinetics, and potential oral bioavailability. Strikingly, B8 demonstrated profound synergy with Mcl-1 Inhibitor VU661013 in acute myeloid leukemia (AML) models, a novel discovery underscoring the therapeutic potential of dual SHP2/Mcl-1 targeting. Our work not only advances the rational design of oral allosteric SHP2 inhibitors but also unveils a critical vulnerability in AML through SHP2-MCL-1 co-targeting, offering a roadmap for combinatorial regimens to improve outcomes in high-risk cancers.

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