LY-3200882
- Soluble in DMSO
- MF: C24H29N5O3
- MW: 435.52
Description
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.
More Information
| Parent CAS No. | 1898283-02-7 |
|---|---|
| Chemical Name | 2-(4-(4-(1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yloxy)pyridin-2-ylamino)pyridin-2-yl)propan-2-ol |
| extra_info | Sold in collaboration with Chemietek |
| SMILES | C1C(OC2C(C3CCOCC3)=NN(C3CC3)C=2)=CC=NC=1NC1C=C(C(O)(C)C)N=CC=1 |
| MFCD | N.A. |
| InChi | InChI=1S/C24H29N5O3/c1-24(2,30)21-13-17(5-9-25-21)27-22-14-19(6-10-26-22)32-20-15-29(18-3-4-18)28-23(20)16-7-11-31-12-8-16/h5-6,9-10,13-16,18,30H,3-4,7-8,11-12H2,1-2H3,(H,25,26,27) |
| InChiKey | PNPFMWIDAKQFPY-UHFFFAOYSA-N |
| CID | 121249291 |
| Short Description | TGF-βR1 inhibitor |
References
- H Pei et al, LY3200882, a novel, highly selective TGFβRI small molecule inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 955.
- G Xu et al. Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors. Eur J Med Chem. 2020 Jul 15;198:112354.
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