Nature Cell Biology. Nichols, R.J., et al. 2018.
Navire Pharma is developing SHP2 inhibitors as effective additions to the therapeutic arsenal for difficult-to-treat cancers.
Science
SHP2 (Src homology region 2-containing protein tyrosine phosphatase, encoded by the PTPN11 gene) is a protein-tyrosine phosphatase that links growth factor, cytokine and integrin signalling with the downstream RAS/ERK MAPK pathway to regulate cellular proliferation and survival. Overactivity of this pathway — often driven by distinct genetic mutations — is the fundamental cause of, or a critical contributor to, many forms of cancer, and is a mechanism of resistance to several targeted therapies. Inhibiting SHP2 offers a novel approach to treat tumors driven by this pathway.
SHP2 also regulates the adaptive immune response by binding to PD-1 and dephosphorylating CD28 and LCK, thereby suppressing T-cell activity against growing tumors. Inhibiting SHP2 may relieve this negative effect, enhancing the patient’s immune response to fight cancer proliferation.
SHP2 Regulation
SHP2 activity is regulated by interaction between its N-terminal SH2 domain and its catalytic (phosphatase) domain. In the inactive form of the protein, the N-terminal SH2 domain blocks the catalytic site, inhibiting phosphatase activity. Upon binding of phosphotyrosyl peptides to the N-SH2 domain, this inhibitory effect is relieved, activating SHP2 signaling.
Navire Approach
Navire Pharma is developing small molecules to treat cancers driven by increased activity of SHP2-regulated pathways. Navire’s compounds act as “molecular glue” by binding to inactive SHP2 and preventing activation, blocking its ability to promote tumor growth.
Publications
Navire is a member of the BridgeBio family
BridgeBio is a clinical-stage biotech company developing novel, genetically targeted therapies to improve the lives of patients. The BridgeBio approach combines a traditional focus on drug development with a unique corporate model, allowing rapid translation of early stage science into medicines that treat disease at its source.
Founded in 2015 by a team of industry veterans, the company has built a portfolio of ten transformative drugs ranging from pre-clinical to late stage development in multiple therapeutic areas including oncology, cardiology, dermatology, neurology, and endocrinology. BridgeBio holds each drug candidate in a distinct subsidiary company to maximize management focus and financial flexibility.
BridgeBio’s focus on scientific excellence and rapid execution aims to translate today’s discoveries into tomorrow’s medicines.
