Research progress in development of SHP2 inhibitors and their application in tumor therapy

doi:10.3969/j.issn.1674-8115.2026.06.003

Abstract

Abstract:

Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), encoded by the PTPN11 gene, is an important molecule in the non-receptor protein tyrosine phosphatase (PTP) family. It can regulate multiple core signaling pathways, including RAS/mitogen-activated protein kinase (RAS/MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1). SHP2 affects the proliferation, differentiation, survival, and apoptosis of tumor cells, and plays an important role in mediating tumor drug resistance. In the tumor microenvironment (TME), SHP2 plays a key role in the regulation of immunosuppression. It can inhibit the activation and effector functions of T cells by participating in the downstream signal transduction of immune checkpoints, while also regulating the status of immune cells such as macrophages and promoting tumor immune escape. Given the dual roles of SHP2 in driving tumor growth and mediating immunosuppression, SHP2-targeted therapy has become a promising anti-tumor strategy. SHP2 inhibitors can not only inhibit the carcinogenic signaling pathways, but also effectively relieve the inhibition of SHP2 on T cells and reprogram the immune microenvironment, thus producing synergistic anti-tumor effects. At the same time, the combined application of SHP2 inhibitors with existing therapies also shows great potential in overcoming drug resistance and improving efficacy, which is an important direction in current tumor treatment research. Based on this, this review summarizes the biological functions and related signaling networks of SHP2, as well as its mechanisms in tumorigenesis and immune escape, and analyzes the research progress of SHP2-targeted drug development and the application prospects of combination treatment strategies, in order to provide new ideas and references for tumor treatment research.

Key words: Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), tumor microenvironment (TME), immunotherapy

CLC Number:

R915

Shen Yuxiao, Li Xiaoguang, Ba Qian. Research progress in development of SHP2 inhibitors and their application in tumor therapy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(6): 713-720.

Figures/Tables 3

TrendMD

References 34

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Compound	NCT number	Planned enrollment/n	Phase	Start date	Status	Indication
TNO155	NCT03114319	227	Ⅰ	2018/09/14	Not yet recruiting	Advanced non-small cell lung cancer, esophageal squamous cell carcinoma, melanoma
JAB-3068	NCT03518554	38	Ⅰ	2018/04/23	Not yet recruiting	Esophageal cancer, head and neck cancer, non-small cell lung cancer, metastatic solid tumor
JAB-3068	NCT03565003	126	Ⅰ/Ⅱ	2018/05/29	Not yet recruiting
RMC-4630	NCT03634982	133	Ⅰ	2018/09/28	Active, not recruiting	Solid tumor
JAB-3312	NCT04045496	24	Ⅰ	2019/09/26	Recruiting	Small cell lung cancer, colorectal cancer, pancreatic ductal carcinoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, breast cancer
JAB-3312	NCT04121286	17	Ⅰ	2020/07/14	Not yet recruiting
BBP-398	NCT04528836	72	Ⅰ	2020/11/12	Terminated	Advanced solid tumor, advanced or metastatic non-small cell lung cancer
BBP-398	NCT05621525	7	Ⅰ	2022/10/18	Terminated
PF07284892	NCT04800822	53	Ⅰ	2021/03/17	Terminated	Solid tumor
SH-3809	NCT04843033	55	Ⅰ	2021/04/02	Recruiting	Solid tumor
ERAS-601	NCT04670679	200	Ⅰ	2020/12/15	Active, not recruiting	Advanced or metastatic non-small cell lung cancer
HBI-2376	NCT05163028	42	Ⅰ	2021/12/13	Active, not recruiting	Colorectal cancer, pancreatic cancer, non-small cell lung cancer, solid tumor
BPI-442096	NCT05369312	230	Ⅰ	2022/06	Not yet recruiting	Colorectal cancer, non-small cell lung cancer, pancreatic cancer, solid tumor
HS-10381	NCT05378178	51	Ⅰ	2022/06/08	Recruiting	Solid tumor
HMPL-415S1	NCT05886374	81	Ⅰ	2023/07/06	Recruiting	Solid tumor

Compound	NCT number	Planned enrollment/n	Phase	Start date	Status	Indication
TNO155	NCT03114319	227	Ⅰ	2018/09/14	Not yet recruiting	Advanced non-small cell lung cancer, esophageal squamous cell carcinoma, melanoma
JAB-3068	NCT03518554	38	Ⅰ	2018/04/23	Not yet recruiting	Esophageal cancer, head and neck cancer, non-small cell lung cancer, metastatic solid tumor
JAB-3068	NCT03565003	126	Ⅰ/Ⅱ	2018/05/29	Not yet recruiting
RMC-4630	NCT03634982	133	Ⅰ	2018/09/28	Active, not recruiting	Solid tumor
JAB-3312	NCT04045496	24	Ⅰ	2019/09/26	Recruiting	Small cell lung cancer, colorectal cancer, pancreatic ductal carcinoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, breast cancer
JAB-3312	NCT04121286	17	Ⅰ	2020/07/14	Not yet recruiting
BBP-398	NCT04528836	72	Ⅰ	2020/11/12	Terminated	Advanced solid tumor, advanced or metastatic non-small cell lung cancer
BBP-398	NCT05621525	7	Ⅰ	2022/10/18	Terminated
PF07284892	NCT04800822	53	Ⅰ	2021/03/17	Terminated	Solid tumor
SH-3809	NCT04843033	55	Ⅰ	2021/04/02	Recruiting	Solid tumor
ERAS-601	NCT04670679	200	Ⅰ	2020/12/15	Active, not recruiting	Advanced or metastatic non-small cell lung cancer
HBI-2376	NCT05163028	42	Ⅰ	2021/12/13	Active, not recruiting	Colorectal cancer, pancreatic cancer, non-small cell lung cancer, solid tumor
BPI-442096	NCT05369312	230	Ⅰ	2022/06	Not yet recruiting	Colorectal cancer, non-small cell lung cancer, pancreatic cancer, solid tumor
HS-10381	NCT05378178	51	Ⅰ	2022/06/08	Recruiting	Solid tumor
HMPL-415S1	NCT05886374	81	Ⅰ	2023/07/06	Recruiting	Solid tumor