9inu

From Proteopedia

Novel PD-L1/VISTA dual inhibitor as potential immunotherapy agents

Structural highlights

9inu is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PD1L1_HUMAN Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation and cytokine production.^[1] ^[2]

Publication Abstract from PubMed

Inhibiting the activity of immune checkpoint proteins to reignite the antitumor activity of immune cells has emerged as a pivotal strategy. PD-L1 and VISTA, as critical proteins governing immune regulation, are concurrently upregulated under conditions such as hypoxia. Through a rational drug design process, P17, a dual-target inhibitor for PD-L1 and VISTA is identified. This inhibitor blocks the signaling pathways of both PD-L1 and VISTA at the protein and cellular levels, thereby reactivating the antitumor function of T cells. P17 displays encouraging attributes in terms of druggability and safety assessments. Notably, P17 demonstrates superior antitumor efficacy compared to single-target inhibitors at equivalent doses in in vivo experiments. More crucially, P17 significantly enhances the infiltration of immune cells. This study not only validates the effectiveness of a dual-target inhibitor strategy against PD-L1 and VISTA, but also identifies P17 as a promising candidate molecule with significant therapeutic potential.

Novel PD-L1/VISTA Dual Inhibitor as Potential Immunotherapy Agents.,Sun C, Cheng Y, Dong J, Hu L, Zhang Y, Shen H, Zhang G, Jiang B, Adam Youssouf S, Min W, Shen Y, Wang L, Deng H, Xiao Y, Yang P J Med Chem. 2025 Jan 9;68(1):156-173. doi: 10.1021/acs.jmedchem.4c01640. Epub , 2024 Dec 28. PMID:39731560^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999 Dec;5(12):1365-9. PMID:10581077 doi:10.1038/70932
↑ Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000 Oct 2;192(7):1027-34. PMID:11015443
↑ Sun C, Cheng Y, Dong J, Hu L, Zhang Y, Shen H, Zhang G, Jiang B, Adam Youssouf S, Min W, Shen Y, Wang L, Deng H, Xiao Y, Yang P. Novel PD-L1/VISTA Dual Inhibitor as Potential Immunotherapy Agents. J Med Chem. 2025 Jan 9;68(1):156-173. PMID:39731560 doi:10.1021/acs.jmedchem.4c01640