PMID- 37023678 OWN - NLM STAT- MEDLINE DCOM- 20230425 LR - 20230425 IS - 1768-3254 (Electronic) IS - 0223-5234 (Linking) VI - 253 DP - 2023 May 5 TI - Discovery of a potent and selective allosteric inhibitor targeting the SHP2 tunnel site for RTK-driven cancer treatment. PG - 115305 LID - S0223-5234(23)00271-4 [pii] LID - 10.1016/j.ejmech.2023.115305 [doi] AB - 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 IC(50) of 10.2 muM 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. CI - Copyright (c) 2023 Elsevier Masson SAS. All rights reserved. FAU - Luo, Ruixiang AU - Luo R AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Fu, Weitao AU - Fu W AD - Department of Computer-Aided Drug Design, Jiangsu Vcare PharmaTech Co. Ltd., Nanjing, 211800, China. FAU - Shao, Jingjing AU - Shao J AD - 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. FAU - Ma, Lin AU - Ma L AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Shuai, Sujuan AU - Shuai S AD - Department of Pharmacy, School of Medicine, Zhejiang University City College, Hangzhou, 310015, China. FAU - Xu, Ying AU - Xu Y AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Jiang, Zheng AU - Jiang Z AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Ye, Zenghui AU - Ye Z AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Zheng, Lulu AU - Zheng L AD - Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310000, China. FAU - Zheng, Lei AU - Zheng L AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Yu, Jie AU - Yu J AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Zhang, Yawen AU - Zhang Y AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Yin, Lina AU - Yin L AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Tu, Linglan AU - Tu L AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Lv, Xinting AU - Lv X AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. FAU - Li, Jie AU - Li J AD - 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: lijie@zucc.edu.cn. FAU - Liang, Guang AU - Liang G AD - 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: wzmcliangguang@163.com. FAU - Chen, Lingfeng AU - Chen L AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China. Electronic address: lfchen@hmc.edu.cn. LA - eng PT - Journal Article DEP - 20230324 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) RN - 0 (Enzyme Inhibitors) SB - IM MH - Humans MH - *Signal Transduction MH - Receptor Protein-Tyrosine Kinases/metabolism MH - *Neoplasms MH - Allosteric Site MH - Carcinogenesis MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11 MH - Enzyme Inhibitors/pharmacology/chemistry OTO - NOTNLM OT - Lead compound OT - Receptor tyrosine kinase OT - SHP2 OT - Structure-activity relationship OT - Structure-based virtual screening COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lingfeng Chen reports financial support was provided by National Natural Science Foundation of China. EDAT- 2023/04/07 06:00 MHDA- 2023/04/25 06:42 CRDT- 2023/04/06 18:09 PHST- 2023/01/13 00:00 [received] PHST- 2023/03/14 00:00 [revised] PHST- 2023/03/22 00:00 [accepted] PHST- 2023/04/25 06:42 [medline] PHST- 2023/04/07 06:00 [pubmed] PHST- 2023/04/06 18:09 [entrez] AID - S0223-5234(23)00271-4 [pii] AID - 10.1016/j.ejmech.2023.115305 [doi] PST - ppublish SO - Eur J Med Chem. 2023 May 5;253:115305. doi: 10.1016/j.ejmech.2023.115305. Epub 2023 Mar 24.