TY - JOUR
T1 - Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3
AU - Tornatore, Laura
AU - Capece, Daria
AU - D'Andrea, Daniel
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.
AU - Kaczmarski, Richard S.
AU - Gabriel, Ian
AU - Oakervee, Heather E.
AU - Kaiser, Martin F.
AU - Wechalekar, Ashutosh
AU - Benjamin, Reuben
AU - Apperley, Jane F.
AU - Auner, Holger W.
AU - Franzoso, Guido
N1 - © 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
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Cancer
KW - GADD45β
KW - Multiple myeloma
KW - NF-κB
KW - Pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85065014616&partnerID=8YFLogxK
U2 - 10.1016/j.toxrep.2019.04.006
DO - 10.1016/j.toxrep.2019.04.006
M3 - Article
VL - 6
SP - 369
EP - 379
JO - Toxicology Reports
JF - Toxicology Reports
ER -