Mechanism of action

Why SHP2

SHP2, also known as PTPN11, is a phosphatase that dephosphorylates substrate proteins. It is an important molecule regulating many cellular functions. In the receptor tyrosine kinase (RTK) pathway, SHP2 effects are upstream of RAS, in mediating tumor proliferation and downstream of the immune checkpoint regulator, Programmed cell death protein 1 (PD-1), in inhibiting the anti-tumor effect of T cells. SHP2 also functions downstream of Colony Stimulating Factor 1 Receptor (CSF1R), in promoting tumor-associated macrophage activity. Thus, targeting SHP2 has potential for multiple anti-tumor effects.

JAB-3312 is highly selective, allosteric inhibitors of SHP2 that can block the RTK/RAS/MAPK signaling pathways and inhibit the growth and proliferation of tumor cells driven by RTK or with KRAS, BRAF Class 3 and NF1 loss of function (LOF) mutations. In addition, JAB-3312 can block PD-1 signaling, enhancing the tumor-killing functions of CD8+ T cells, and relieve immunosuppression in the tumor microenvironment from tumor-associated macrophages resulting in overall anti-tumor effects.

Indication

1.2million
patients benefited

Results from studies to date suggest that JAB-3312 may be effective in patients with non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, colorectal cancer, pancreatic cancer harboring specific gene mutations, and patients with Class 3 BRAF-mutated, or NF1 LOF mutated solid tumors. Estimates from the global tumor incidence data from 2019 indicate that 1.2 million patients with advanced solid tumors worldwide may benefit from SHP2 inhibitor monotherapy.

Also promising are synergistic effects for SHP2 inhibitors used in combination with a variety of targeted therapies and immunotherapies, such as KRAS/EGFR/ALK inhibitors, and PD-1 antibody, that would expand this potential benefit to even more patients.

Clinical Trial

Combination Therapy

Assets

Partners

Region

Phase

Indications

Registration Information

JAB-3312

Glecirasib (KRAS G12Ci)

China IIa Advanced Solid Tumor

ClinicalTrials: NCT05288205

CDE Number: CTR20220587

JAB-3312+Glecirasib VS Tirelizumab+Pemetrexed+Carboplatin China

III

NSCLC

ClinicalTrials: NCT06416410

References

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  • Nichols, R.J., et al., RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol, 2018. 20(9): p. 1064-1073.
  • Yaeger, R. and D.B. Solit, Overcoming Adaptive Resistance to KRAS Inhibitors Through Vertical Pathway Targeting. Clin Cancer Res, 2020. 26(7): p. 1538-1540.
  • Fedele, C., et al., SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models. Cancer Discov, 2018. 8(10): p. 1237-1249.
  • Ruess, D.A., et al., Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med, 2018. 24(7): p. 954-960.
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