2. Academic Validation
  3. Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3

Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3

  • Toxicol Rep. 2019 Apr 19;6:369-379. doi: 10.1016/j.toxrep.2019.04.006.
Laura Tornatore 1,  Daria Capece 1,  Daniel D'Andrea 1,  Federica Begalli 1,  Daniela Verzella 1,  Jason Bennett 1,  Gary Acton 2,  Elizabeth A Campbell 3,  James Kelly 4,  Michael Tarbit 5,  Nigel Adams 6,  Selina Bannoo 1,  Antonio Leonardi 7,  Annamaria Sandomenico 8,  Domenico Raimondo 9,  Menotti Ruvo 8,  Angela Chambery 10,  Metod Oblak 11,  Magda J Al-Obaidi 12,  Richard S Kaczmarski 13,  Ian Gabriel 12,  Heather E Oakervee 14,  Martin F Kaiser 15,  Ashutosh Wechalekar 16,  Reuben Benjamin 17,  Jane F Apperley 18,  Holger W Auner 18 19,  Guido Franzoso 1
Affiliations

Affiliations

  • 1 CCSI, Department of Medicine, Imperial College London, London, UK.
  • 2 Cancer Research UK Centre for Drug Development, London, UK.
  • 3 C&C Management Consulting Ltd, Exmouth, UK.
  • 4 Alpha Preclinical Consultancy, Halifax, UK.
  • 5 Independent Consultant, Royston, UK.
  • 6 In2Phase Ltd, Welwyn Garden City, UK.
  • 7 Department of Molecular Medicine, University of Naples Federico II, Naples, Italy.
  • 8 IBB-CNR and CIRPeB, "Federico II" University of Naples, Naples, Italy.
  • 9 Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  • 10 DiSTABiF, University of Campania "Luigi Vanvitelli", Caserta, Italy.
  • 11 West Middlesex University Hospital, Isleworth, Greater London, UK.
  • 12 Haematology Department, Chelsea and Westminster Hospital, London, UK.
  • 13 London Haematology Limited, London, UK.
  • 14 Barts Cancer Centre, St Bartholomew's Hospital London, London, UK.
  • 15 Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
  • 16 Royal Free London NHS Foundation Trust, London, UK.
  • 17 Department of Haematology, King's College Hospital, London, UK.
  • 18 Centre for Haematology, Imperial College, London, UK.
  • 19 Cancer Cell Protein Metabolism, Department of Medicine, Imperial College London, London, UK.
PMID: 31080744 DOI: 10.1016/j.toxrep.2019.04.006
Abstract

Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)β/NF-κB Inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)β/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo, ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic Anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers.

Keywords

Cancer; GADD45β; Multiple myeloma; NF-κB; Pharmacology.

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