Imperial College London
Portrait Picture

Professor Guido Franzoso

Faculty of Medicine, Department of Immunology and Inflammation

Chair in Inflammation and Signal Transduction
 
 
 
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Contact

 

+44 (0)20 3313 8421g.franzoso Website

 
 
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Assistant

 

Miss Anjli Jagpal +44 (0)20 3313 3152

 
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Location

 

5N1Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Tornatore:2019:10.1016/j.toxrep.2019.04.006,
author = {Tornatore, L and Capece, D and D'Andrea, D and Begalli, F and Verzella, D and Bennett, J and Acton, G and Campbell, EA and Kelly, J and Tarbit, M and Adams, N and Bannoo, S and Leonardi, A and Sandomenico, A and Raimondo, D and Ruvo, M and Chambery, A and Oblak, M and Al-Obaidi, MJ and Kaczmarski, RS and Gabriel, I and Oakervee, HE and Kaiser, MF and Wechalekar, A and Benjamin, R and Apperley, JF and Auner, HW and Franzoso, G},
doi = {10.1016/j.toxrep.2019.04.006},
journal = {Toxicology Reports},
pages = {369--379},
title = {Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3},
url = {http://dx.doi.org/10.1016/j.toxrep.2019.04.006},
volume = {6},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
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.
AU  - Tornatore,L
AU  - Capece,D
AU  - D'Andrea,D
AU  - Begalli,F
AU  - Verzella,D
AU  - Bennett,J
AU  - Acton,G
AU  - Campbell,EA
AU  - Kelly,J
AU  - Tarbit,M
AU  - Adams,N
AU  - Bannoo,S
AU  - Leonardi,A
AU  - Sandomenico,A
AU  - Raimondo,D
AU  - Ruvo,M
AU  - Chambery,A
AU  - Oblak,M
AU  - Al-Obaidi,MJ
AU  - Kaczmarski,RS
AU  - Gabriel,I
AU  - Oakervee,HE
AU  - Kaiser,MF
AU  - Wechalekar,A
AU  - Benjamin,R
AU  - Apperley,JF
AU  - Auner,HW
AU  - Franzoso,G
DO  - 10.1016/j.toxrep.2019.04.006
EP  - 379
PY  - 2019///
SN  - 2214-7500
SP  - 369
TI  - Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3
T2  - Toxicology Reports
UR  - http://dx.doi.org/10.1016/j.toxrep.2019.04.006
UR  - http://hdl.handle.net/10044/1/69218
VL  - 6
ER  -
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