Preclinical Activity and Pharmacokinetic/Pharmacodynamic Relationship for a Series of Novel Benzenesulfonamide Perforin Inhibitors

  • ACS Pharmacol Transl Sci. 2022 May 31;5(6):429-439. doi: 10.1021/acsptsci.2c00009.
Kate H Gartlan  1 ,  Jagdish K Jaiswal  2  3 ,  Matthew R Bull  2  3 ,  Hedieh Akhlaghi  4 ,  Vivien R Sutton  4  5 ,  Kylie A Alexander  1 ,  Karshing Chang  1 ,  Geoffrey R Hill  1  6 ,  Christian K Miller  2  3 ,  Patrick D O'Connor  2  3 ,  Jiney Jose  2  3 ,  Joseph A Trapani  4  5 ,  Susan A Charman  7 ,  Julie A Spicer  2  3  8 ,  Stephen M F Jamieson  2  3  8
Affiliations
  • 1. QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4006, Australia.
  • 2. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 3. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 4. Cancer Immunology Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia.
  • 5. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3052, Australia.
  • 6. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States.
  • 7. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 8. Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
PMID: 35711815 DOI: 10.1021/acsptsci.2c00009
Abstract

Perforin is a key effector of lymphocyte-mediated cell death pathways and contributes to transplant rejection of immunologically mismatched grafts. We have developed a novel series of benzenesulfonamide (BZS) inhibitors of perforin that can mitigate graft rejection during allogeneic bone marrow/stem cell transplantation. Eight such perforin inhibitors were tested for their murine pharmacokinetics, plasma protein binding, and their ability to block perforin-mediated lysis in vitro and to block the rejection of major histocompatibility complex (MHC)-mismatched mouse bone marrow cells. All compounds showed >99% binding to plasma proteins and demonstrated perforin inhibitory activity in vitro and in vivo. A lead compound, compound 1, that showed significant increases in allogeneic bone marrow preservation was evaluated for its plasma pharmacokinetics and in vivo efficacy at multiple dosing regimens to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship. The strongest PK/PD correlation was observed between perforin inhibition in vivo and time that total plasma concentrations remained above 900 μM, which correlates to unbound concentrations similar to 3× the unbound in vitro IC90 of compound 1. This PK/PD relationship will inform future dosing strategies of BZS perforin inhibitors to maintain concentrations above 3× the unbound IC90 for as long as possible to maximize efficacy and enhance progression toward clinical evaluation.

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