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

Laura Tornatore, Daria Capece, Daniel D'Andrea, Federica Begalli, Daniela Verzella, Jason Bennett, Gary Acton, Elizabeth A. Campbell, James Kelly, Michael Tarbit, Nigel Adams, Selina Bannoo, Antonio Leonardi, Annamaria Sandomenico, Domenico Raimondo, Menotti Ruvo, Angela Chambery, Metod Oblak, Magda J. Al-Obaidi, Richard S. Kaczmarski & 8 others Ian Gabriel, Heather E. Oakervee, Martin F. Kaiser, Ashutosh Wechalekar, Reuben Benjamin, Jane F. Apperley, Holger W. Auner, Guido Franzoso

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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.
Original languageEnglish
Pages (from-to)369-379
Number of pages11
JournalToxicology Reports
Volume6
Early online date19 Apr 2019
DOIs
Publication statusPublished - 2019

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Multiple Myeloma
Toxicology
Toxicity
Oncology
Pharmacology
Safety
MAP Kinase Kinase 7
Cells
Pharmacodynamics
Cell Survival
Pharmacokinetics
Heterografts
Pharmaceutical Preparations
Neoplasms
Drug Industry
Phosphotransferases
Drug Delivery Systems
Biological Availability
DNA Damage
Half-Life

Bibliographical note

© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).T

Keywords

  • Cancer
  • GADD45β
  • Multiple myeloma
  • NF-κB
  • Pharmacology

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3. / Tornatore, Laura ; Capece, Daria ; D'Andrea, Daniel ; Begalli, Federica; Verzella, Daniela ; Bennett, Jason; Acton, Gary; Campbell, Elizabeth A. ; Kelly, James ; Tarbit, Michael ; Adams, Nigel ; Bannoo, Selina ; Leonardi, Antonio ; Sandomenico, Annamaria ; Raimondo, Domenico; Ruvo, Menotti ; Chambery, Angela ; Oblak, Metod ; Al-Obaidi, Magda J. ; Kaczmarski, Richard S. ; Gabriel, Ian; Oakervee, Heather E. ; Kaiser, Martin F.; Wechalekar, Ashutosh ; Benjamin, Reuben ; Apperley, Jane F. ; Auner, Holger W. ; Franzoso, Guido .

In: Toxicology Reports, Vol. 6, 2019, p. 369-379.

Research output: Contribution to journalArticle

Tornatore, L, Capece, D, D'Andrea, D, Begalli, F, Verzella, D, Bennett, J, Acton, G, Campbell, EA, Kelly, J, Tarbit, M, Adams, N, Bannoo, S, Leonardi, A, Sandomenico, A, Raimondo, D, Ruvo, M, Chambery, A, Oblak, M, Al-Obaidi, MJ, Kaczmarski, RS, Gabriel, I, Oakervee, HE, Kaiser, MF, Wechalekar, A, Benjamin, R, Apperley, JF, Auner, HW & Franzoso, G 2019, 'Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3' Toxicology Reports, vol. 6, pp. 369-379. https://doi.org/10.1016/j.toxrep.2019.04.006
Tornatore, Laura ; Capece, Daria ; D'Andrea, Daniel ; Begalli, Federica ; Verzella, Daniela ; Bennett, Jason ; Acton, Gary ; Campbell, Elizabeth A. ; Kelly, James ; Tarbit, Michael ; Adams, Nigel ; Bannoo, Selina ; Leonardi, Antonio ; Sandomenico, Annamaria ; Raimondo, Domenico ; Ruvo, Menotti ; Chambery, Angela ; Oblak, Metod ; Al-Obaidi, Magda J. ; Kaczmarski, Richard S. ; Gabriel, Ian ; Oakervee, Heather E. ; Kaiser, Martin F. ; Wechalekar, Ashutosh ; Benjamin, Reuben ; Apperley, Jane F. ; Auner, Holger W. ; Franzoso, Guido . / Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3. In: Toxicology Reports. 2019 ; Vol. 6. pp. 369-379.
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AU - Begalli, Federica

AU - Verzella, Daniela

AU - Bennett, Jason

AU - Acton, Gary

AU - Campbell, Elizabeth A.

AU - Kelly, James

AU - Tarbit, Michael

AU - Adams, Nigel

AU - Bannoo, Selina

AU - Leonardi, Antonio

AU - Sandomenico, Annamaria

AU - Raimondo, Domenico

AU - Ruvo, Menotti

AU - Chambery, Angela

AU - Oblak, Metod

AU - Al-Obaidi, Magda J.

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AU - Gabriel, Ian

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AU - Wechalekar, Ashutosh

AU - Benjamin, Reuben

AU - Apperley, Jane F.

AU - Auner, Holger W.

AU - Franzoso, Guido

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