Comprehensive in vitro characterization of PD-L1 small molecule inhibitors

  • Sci Rep. 2019 Aug 27;9(1):12392. doi: 10.1038/s41598-019-48826-6.
Aravindhan Ganesan  1 ,  Marawan Ahmed  1 ,  Isobel Okoye  2 ,  Elena Arutyunova  3 ,  Dinesh Babu  1 ,  William L Turnbull  4 ,  Joydeb Kumar Kundu  5 ,  Justin Shields  6 ,  Katharine Cheryl Agopsowicz  7 ,  Lai Xu  2 ,  Yasser Tabana  1 ,  Nutan Srivastava  1 ,  Guangzhi Zhang  2 ,  Tae Chul Moon  1 ,  Alexandr Belovodskiy  5 ,  Mostofa Hena  5 ,  Appan Srinivas Kandadai  5 ,  Seyedeh Nargess Hosseini  4 ,  Mary Hitt  6  7  8 ,  John Walker  8 ,  Michael Smylie  8 ,  Frederick G West  4  7 ,  Arno G Siraki  1  7 ,  M Joanne Lemieux  3  7 ,  Shokrollah Elahi  2  6  7  9 ,  James A Nieman  5 ,  D Lorne Tyrrell  5  6  9 ,  Michael Houghton  5  6  9 ,  Khaled Barakat  10  11  12  13
Affiliations
  • 1. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
  • 2. Department of Dentistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.
  • 3. Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.
  • 4. Department of Chemistry, Faculty of Science, University of Alberta, Edmonton, AB, Canada.
  • 5. Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada.
  • 6. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
  • 7. Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada.
  • 8. Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.
  • 9. Department of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.
  • 10. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. [email protected].
  • 11. Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada. [email protected].
  • 12. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada. [email protected].
  • 13. Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada. [email protected].
PMID: 31455818 DOI: 10.1038/s41598-019-48826-6
Abstract

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a powerful strategy in Cancer Immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies have individually disclosed several promising PD-1/PD-L1 inhibitors, whose detailed experimental data are not publicly disclosed. In this work, we report the rigorous and systematic in vitro characterization of a selected set of potent PD-1/PD-L1 macrocyclic peptide (BMSpep-57) and small-molecule inhibitors (BMS-103, BMS-142) from BMS and a peptidomimetic small-molecule inhibitor from Aurigene (Aurigene-1) using a series of biochemical and cell-based assays. Our results confirm that BMS-103 and BMS-142 are strongly active in biochemical assays; however, their acute cytotoxicity greatly compromised their immunological activity. On the Other hand, Aurigene-1 did not show any activity in both biochemical and immunological assays. Furthermore, we also report the discovery of a small-molecule immune modulator, whose mode-of-action is not clear; however, it exhibits favorable drug-like properties and strong immunological activity. We hope that the results presented here will be useful in guiding the development of next-generation PD-1/PD-L1 small molecule inhibitors.

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