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SHP2 inhibitor

Jacobio has independently developed Src homology 2-containing phosphotyrosine phosphatase (SHP2) inhibitors, JAB-3068 and JAB-3312, using the drug design platform based on the allosteric binding site. Jacobio is currently conducting clinical trials in China and the United States evaluating these inhibitors.

JAB-3068 is the second SHP2 inhibitor approved by the FDA to enter clinical development. JAB-3312, the second generation SHP2 inhibitor designed by Jacobio has more potent anti-tumor activities. Both compounds have been granted orphan drug designation by the FDA for the treatment of esophageal cancer (including esophageal squamous cell carcinoma).

Mechanism of Action

JAB-3068 is the second SHP2 inhibitor approved by the FDA to enter clinical development. JAB-3312, the second generation SHP2 inhibitor designed by Jacobio has more potent anti-tumor activities. Both compounds have been granted orphan drug designation by the FDA for the treatment of esophageal cancer (including esophageal squamous cell carcinoma).

AB-3068 and JAB-3312 are highly selective, allosteric inhibitors for SHP2 phosphatase, that can block 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-3068 and JAB-3312 can enhance the tumor-killing functions of CD8+T cells by blocking PD-1 inhibitory signaling. This signal blockade inhibits the functions of tumor-associated macrophages that, in turn, relieves immunosuppression in the tumor microenvironment resulting in anti-tumor effects.

Indications

Based on preclinical data supporting mechanism-based SHP2 inhibitor sensitivity of cancers harboring specific gene mutations including KRAS, BRAF Class 3, and NF1 LOF mutations, JAB-3068 and JAB-3312 are being evaluated in patient populations enriched for such mutations including non-small cell lung cancer; head and neck squamous cell carcinoma; esophageal squamous cell carcinoma; colorectal cancer; and pancreatic cancers. As of 2019, these tumor types comprise a global tumor incidence of 1.2 million patients. In addition, preclinical data supports mechanism-based combination activity of SHP2 inhibitors with a wide variety of targeted therapies including KRASi, TKIs (e.g. EGFRi, HER2i, ALKi), and MEKi and immune checkpoint therapies including PD-(L)1 antagonists.

Clinical Trials
Monotherapy clinical trials
Assets Region Phase Indication Registration information
JAB-3068 U.S. I Advanced solid tumors ClinicalTrials: NCT03518554
China  I/IIa NSCLC, ESCC, CDE number: CTR20181038
ClinicalTrials: NCT04721223
HNSCC
JAB-3312  U.S.  IIa Tumors harboring NF1 LOF or
BRAF Class 3 mutations
ClinicalTrails: NCT04045496
U.S.  I Advanced solid tumors
China  I Advanced solid tumors CDE number: CTR20192032
ClinicalTrails: NCT04121286
 
Combination therapy clinical trials
Assets Partner Region  Phase  Indication Registration information
JAB-3068 Toripalimab
(anti- PD-1 antibody)
China Ib/IIa Advanced solid tumors ClinicalTrials: NCT04721223
CDE number: CTR20210091
JAB-3312 Pembrolizumab
(anti- PD-1 antibody)
Binimetinib
(MEK inhibitor)
U.S.  I/IIa Advanced solid tumors ClinicalTrails: NCT04720976
Partnership:AbbVie Learn More
 
Reference
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  2. 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.
  3. 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.
  4. Fedele, C., et al., SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models. Cancer Discov, 2018. 8(10): p. 1237-1249.
  5. 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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