2. Academic Validation
  3. Discovery of a potent and selective allosteric inhibitor targeting the SHP2 tunnel site for RTK-driven cancer treatment

Discovery of a potent and selective allosteric inhibitor targeting the SHP2 tunnel site for RTK-driven cancer treatment

  • Eur J Med Chem. 2023 May 5;253:115305. doi: 10.1016/j.ejmech.2023.115305.
Ruixiang Luo 1,  Weitao Fu 2,  Jingjing Shao 3,  Lin Ma 1,  Sujuan Shuai 4,  Ying Xu 1,  Zheng Jiang 1,  Zenghui Ye 1,  Lulu Zheng 5,  Lei Zheng 1,  Jie Yu 1,  Yawen Zhang 1,  Lina Yin 1,  Linglan Tu 1,  Xinting Lv 1,  Jie Li 6,  Guang Liang 7,  Lingfeng Chen 8
Affiliations

Affiliations

  • 1 Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China.
  • 2 Department of Computer-Aided Drug Design, Jiangsu Vcare PharmaTech Co. Ltd., Nanjing, 211800, China.
  • 3 Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 4 Department of Pharmacy, School of Medicine, Zhejiang University City College, Hangzhou, 310015, China.
  • 5 Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310000, China.
  • 6 Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Department of Pharmacy, School of Medicine, Zhejiang University City College, Hangzhou, 310015, China. Electronic address: [email protected].
  • 7 Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: [email protected].
  • 8 Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. Electronic address: [email protected].
PMID: 37023678 DOI: 10.1016/j.ejmech.2023.115305
Abstract

Src homology 2 domain-containing Phosphatase 2 (SHP2) is a cytoplasmic protein tyrosine Phosphatase (PTP) that regulates signal transduction of Receptor Tyrosine Kinases (RTKs). Abnormal SHP2 activity is associated with tumorigenesis and metastasis. Because SHP2 contains multiple allosteric sites, identifying inhibitors at specific allosteric binding sites remains challenging. Here, we used structure-based virtual screening to directly search for the SHP2 "tunnel site" allosteric inhibitor. A novel hit (70) was identified as the SHP2 allosteric inhibitor with an IC50 of 10.2 μM against full-length SHP2. Derivatization of hit compound 70 using molecular modeling-guided structure-based modification allowed the discovery of an effective and selective SHP2 Inhibitor, compound 129, with 122-fold improved potency compared to the hit. Further studies revealed that 129 effectively inhibited signaling in multiple RTK-driven cancers and RTK inhibitor-resistant Cancer cells. Remarkably, 129 was orally bioavailable (F = 55%) and significantly inhibited tumor growth in haematological malignancy. Taken together, compound 129 developed in this study may serve as a promising lead or candidate for cancers bearing RTK oncogenic drivers and SHP2-related diseases.

Keywords

Lead compound; Receptor tyrosine kinase; SHP2; Structure-activity relationship; Structure-based virtual screening.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149241
    SHP2 Inhibitor