2. Academic Validation
  3. Comprehensive in vitro characterization of PD-L1 small molecule inhibitors

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

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. kbarakat@ualberta.ca.
  • 11 Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada. kbarakat@ualberta.ca.
  • 12 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada. kbarakat@ualberta.ca.
  • 13 Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada. kbarakat@ualberta.ca.
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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