TARGET, is highly expressed in dorsal root ganglion (DRG) neurons, microglia in the central nervous system (CNS), and CD8+ T cells in the immune system.
In multiple animal neuropathy models, TARGET knockout mice exhibited increased tolerance to mechanical pain, heat pain, and cold pain. Moreover, the tumor microenvironment enhances TARGET ligand expression, leading to immunosuppression by inhibiting CD8+ T cell activation and proliferation, thus promoting tumor growth.
Consequently, developing antagonists against TARGET holds promise for reducing chemotherapy-induced peripheral neuropathy (CiPN), enhancing CD8+ T cell inhibition of tumor function, and serving as a therapeutic agent alongside antitumor medications.
Mechanism of Action for CiPN/tumor
￭ TARGET is a GPCR mainly expressed in T cells and CNS. Its endogenous ligand is elevated during nerve injury and in tumor patients, playing key roles in neuropathic pain and carcinogenesis/metastasis. The loss function of TARGET alleviates allodynia and inhibits tumor growth & metastasis.
￭ IPG6620 is a potential first-in-class small molecule antagonist of TARGET in CiPN indication and also modulates tumor microenvironment and inhibits tumor growth & metastasis.
Mechanism of Action for tumor
￭ CD8+ T cells are the Swiss Army knife which kill tumor cells when activated.
￭ TARGET, also expressed in CD8+ T cells, is an inhibitory receptor that suppresses CD8+ T cell cytotoxic function via disruption of early TCR signaling.
￭ The synthesis enzyme of TARGET ligand has been exploited by tumor cells to promote growth.
￭ IPG6620, function as antagonist of TARGET, would resume the inhibition of CD8+ T cells in tumor micro-environment.