| Structural highlights
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
Although heavily studied, the subject of anti-PD-L1 small-molecule inhibitors is still elusive. Here we present a systematic overview of the principles behind successful anti-PD-L1 small-molecule inhibitor design on the example of the m-terphenyl scaffold, with a particular focus on the neglected influence of the solubilizer tag on the overall affinity toward PD-L1. The inhibitor developed according to the proposed guidelines was characterized through its potency in blocking PD-1/PD-L1 complex formation in homogeneous time-resolved fluorescence and cell-based assays. The affinity is also explained based on the crystal structure of the inhibitor itself and its costructure with PD-L1 as well as a molecular modeling study. Our results structuralize the knowledge related to the strong pharmacophore feature of the m-terphenyl scaffold preferential geometry and the more complex role of the solubilizer tag in PD-L1 homodimer stabilization.
Solubilizer Tag Effect on PD-L1/Inhibitor Binding Properties for m-Terphenyl Derivatives.,Surmiak E, Zaber J, Plewka J, Wojtanowicz G, Kocik-Krol J, Kruc O, Muszak D, Rodriguez I, Musielak B, Viviano M, Castellano S, Skalniak L, Magiera-Mularz K, Holak TA, Kalinowska-Tluscik J ACS Med Chem Lett. 2023 Dec 14;15(1):36-44. doi: 10.1021/acsmedchemlett.3c00306. , eCollection 2024 Jan 11. PMID:38229762[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
- ↑ Surmiak E, Ząber J, Plewka J, Wojtanowicz G, Kocik-Krol J, Kruc O, Muszak D, Rodríguez I, Musielak B, Viviano M, Castellano S, Skalniak L, Magiera-Mularz K, Holak TA, Kalinowska-Tłuścik J. Solubilizer Tag Effect on PD-L1/Inhibitor Binding Properties for m-Terphenyl Derivatives. ACS Med Chem Lett. 2023 Dec 14;15(1):36-44. PMID:38229762 doi:10.1021/acsmedchemlett.3c00306
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