LY-3200882 is a next generation small molecule inhibitor of TGF-β receptor type 1 (TGFβRI) and a promising immune modulatory agent. It is a potent, highly selective inhibitor of TGFβRI embodied in a structural platform with a synthetically scalable route, in an ATP competitive fashion to the serine-threonine kinase domain of TGFβRI. Mechanism of action studies reveal that LY-3200882 inhibits various pro-tumorigenic activities. It potently inhibits TGFβ mediated SMAD phosphorylation in vitro in tumor and immune cells and in vivo in subcutaneous tumors in a dose dependent fashion. In preclinical tumor models, LY-3200882 showed potent anti-tumor activity in the orthotopic 4T1-LP model of triple negative breast cancer and this activity correlated with enhanced tumor infiltrating lymphocytes in the tumor microenvironment. Durable tumor regressions in the orthotopic 4T1-LP model were observed and rechallenge of congenic tumors resulted in complete rejection in all mice. In in vitro immune suppression assays, LY-3200882 has shown the ability to rescue TGFβ1 suppressed or T regulatory cell suppressed naïve T cell activity and restore proliferation. It also showed anti-metastatic activity in vitro in migration assays as well as in vivo in an experimental metastasis tumor model (intravenous EMT6-LM2 model of triple negative breast cancer). Finally, LY-3200882 shows combinatorial anti-tumor benefits with checkpoint inhibition (anti-PD-L1) in the syngeneic CT26 model.

KEYWORDS: LY-3200882 | Supplier | TGF-βR1 inhibitor | LY3200882 | LY 3200882 | CT-LY320 | CAS [1898283-02-7] | TGF-β | TGF-βR | Antagonist | Receptors