Structural Basis for Small Molecule Targeting of the Programmed Death Ligand 1 (PD-L1)

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Apr 16

PMID 27083005

Citations 152

Authors

Krzysztof M Zak

Przemyslaw Grudnik

Katarzyna Guzik

Bartosz J Zieba

Bogdan Musielak

Alexander Domling

Grzegorz Dubin

Tad A Holak

Affiliations

Soon will be listed here.

Abstract

Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction "hot spots" on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery.

Citing Articles

A Comparative Molecular Dynamics Study of Food-Derived Compounds as PD-L1 Inhibitors: Insights Across Six Flavonoid Subgroups.

Jiang D, Kwon H, Kwon O, Choi Y Molecules. 2025; 30(4).

PMID: 40005217 PMC: 11858612. DOI: 10.3390/molecules30040907.

Advancements in drug discovery: integrating CADD tools and drug repurposing for PD-1/PD-L1 axis inhibition.

Sobral P, Carvalho T, Izadi S, Castilho A, Silva Z, Videira P RSC Adv. 2025; 15(4):2298-2316.

PMID: 39867321 PMC: 11755407. DOI: 10.1039/d4ra08245a.

Targeted Delivery of BMS-1166 for Enhanced Breast Cancer Immunotherapy.

Yu Z, Zhou Z, Zhao Y Int J Nanomedicine. 2025; 20():293-308.

PMID: 39802387 PMC: 11725277. DOI: 10.2147/IJN.S497089.

Antitumor Activity of the PD-1/PD-L1 Inhibitor SCL-1 in Various Mouse Tumor Models.

Ashizawa T, Iizuka A, Kanematsu A, Ando T, Maeda C, Miyata H In Vivo. 2024; 39(1):80-95.

PMID: 39740910 PMC: 11705142. DOI: 10.21873/invivo.13805.

Metabolizable alloy clusters assemble nanoinhibitor for enhanced radiotherapy of tumor by hypoxia alleviation and intracellular PD-L1 restraint.

Ding G, Liu S, Yang X, Lv H, Jia M, Li J J Nanobiotechnology. 2024; 22(1):774.

PMID: 39696327 PMC: 11657501. DOI: 10.1186/s12951-024-03057-4.

References

Herbst R, Soria J, Kowanetz M, Fine G, Hamid O, Gordon M . Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014; 515(7528):563-7. PMC: 4836193. DOI: 10.1038/nature14011. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Topalian S, Drake C, Pardoll D . Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015; 27(4):450-61. PMC: 4400238. DOI: 10.1016/j.ccell.2015.03.001. View

Arkin M, Wells J . Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov. 2004; 3(4):301-17. DOI: 10.1038/nrd1343. View

Bista M, Kowalska K, Janczyk W, Domling A, Holak T . Robust NMR screening for lead compounds using tryptophan-containing proteins. J Am Chem Soc. 2009; 131(22):7500-1. DOI: 10.1021/ja901863h. View

Cheng X, Veverka V, Radhakrishnan A, Waters L, Muskett F, Morgan S . Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem. 2013; 288(17):11771-85. PMC: 3636866. DOI: 10.1074/jbc.M112.448126. View

Arkin M, Tang Y, Wells J . Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol. 2014; 21(9):1102-14. PMC: 4179228. DOI: 10.1016/j.chembiol.2014.09.001. View

Evans P . Scaling and assessment of data quality. Acta Crystallogr D Biol Crystallogr. 2005; 62(Pt 1):72-82. DOI: 10.1107/S0907444905036693. View

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

10.

Mahoney K, Rennert P, Freeman G . Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015; 14(8):561-84. DOI: 10.1038/nrd4591. View

11.

Sunshine J, Taube J . PD-1/PD-L1 inhibitors. Curr Opin Pharmacol. 2015; 23:32-8. PMC: 4516625. DOI: 10.1016/j.coph.2015.05.011. View

12.

de Beer T, Berka K, Thornton J, Laskowski R . PDBsum additions. Nucleic Acids Res. 2013; 42(Database issue):D292-6. PMC: 3965036. DOI: 10.1093/nar/gkt940. View

13.

Zak K, Kitel R, Przetocka S, Golik P, Guzik K, Musielak B . Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1. Structure. 2015; 23(12):2341-2348. PMC: 4752817. DOI: 10.1016/j.str.2015.09.010. View

14.

Sharma P, Allison J . The future of immune checkpoint therapy. Science. 2015; 348(6230):56-61. DOI: 10.1126/science.aaa8172. View

15.

Lin D, Tanaka Y, Iwasaki M, Gittis A, Su H, Mikami B . The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci U S A. 2008; 105(8):3011-6. PMC: 2268576. DOI: 10.1073/pnas.0712278105. View

16.

Matulis D, Kranz J, Salemme F, Todd M . Thermodynamic stability of carbonic anhydrase: measurements of binding affinity and stoichiometry using ThermoFluor. Biochemistry. 2005; 44(13):5258-66. DOI: 10.1021/bi048135v. View

17.

Stoll R, Renner C, Hansen S, Palme S, Klein C, Belling A . Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53. Biochemistry. 2001; 40(2):336-44. DOI: 10.1021/bi000930v. View

18.

Adams P, Afonine P, Bunkoczi G, Chen V, Davis I, Echols N . PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 2):213-21. PMC: 2815670. DOI: 10.1107/S0907444909052925. View

19.

Domling A, Holak T . Programmed death-1: therapeutic success after more than 100 years of cancer immunotherapy. Angew Chem Int Ed Engl. 2014; 53(9):2286-8. PMC: 4104593. DOI: 10.1002/anie.201307906. View

20.

Powles T, Eder J, Fine G, Braiteh F, Loriot Y, Cruz C . MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014; 515(7528):558-62. DOI: 10.1038/nature13904. View