Preclinical toxicology and safety pharmacology of the first-in-class GADD45beta/MKK7 inhibitor and clinical candidate, DTP3(45 visite) 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
Parole chiave: Cancer, Gadd45beta, Multiple Myeloma, Nf-Kappab, Pharmacology
*** IBB - CNR *** CCSI, Department of Medicine, Imperial College London, London, UK., Cancer Research UK Centre for Drug Development, London, UK., C&C Management Consulting Ltd, Exmouth, UK., Alpha Preclinical Consultancy, Halifax, UK., Independent Consultant, Royston, UK., In2Phase Ltd, Welwyn Garden City, UK., Department of Molecular Medicine, University of Naples Federico II, Naples, Italy., IBB-CNR and CIRPeB, "Federico II" University of Naples, Naples, Italy., Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy., DiSTABiF, University of Campania "Luigi Vanvitelli", Caserta, Italy., West Middlesex University Hospital, Isleworth, Greater London, UK., Haematology Department, Chelsea and Westminster Hospital, London, UK., London Haematology Limited, London, UK., Barts Cancer Centre, St Bartholomew's Hospital London, London, UK., Division of Molecular Pathology, The Institute of Cancer Research, London, UK., Royal Free London NHS Foundation Trust, London, UK., Department of Haematology, King's College Hospital, London, UK., Centre for Haematology, Imperial College, London, UK., Cancer Cell Protein Metabolism, Department of Medicine, Imperial College London, London, UK.,
Aberrant NF-kappaB 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 IkappaBalpha kinase (IKK)beta/NF-kappaB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-kappaB-targeting drugs. To overcome this barrier to therapeutic NF-kappaB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)beta/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-kappaB 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-kappaB survival signalling in MM and potentially other NF-kappaB-driven cancers.
Kim YH, Shin SW, Pellicano R, Fagoonee S, Choi IJ, Kim YI, Park B, Choi JM, Kim SG, Choi J, Park JY, Oh S, Yang HJ, Lim JH, Im JP, Kim JS, Jung HC, Ponzetto A, Figura N, Malfertheiner P, Choi IJ, Kook MC, Kim YI, Cho SJ, Lee JY, Kim CG, Park B, Nam BH, Bae SE, Choi KD, Choe J, Kim SO, Na HK, Choi JY, Ahn JY, Jung KW, Lee J, Kim DH, Chang HS, Song HJ, Lee GH, Jung HY, Seta T, Takahashi Y, Noguchi Y, Shikata S, Sakai T, Sakai K, Yamashita Y, Nakayama T, Leja M, Park JY, Murillo R, Liepniece-karele I, Isajevs S, Kikuste I, Rudzite D, Krike P, Parshutin S, Polaka I, Kirsners A, Santare D, Folkmanis V, Daugule I, Plummer M, Herrero R, Tsukamoto T, Nakagawa M, Kiriyama Y, Toyoda T, Cao X, Corral JE, Mera R, Dye CW, Morgan DR, Lee YC, Lin JT, Garcia Martin R, Matia Cubillo A, Lee SH, Park JM, Han YM, Ko WJ, Hahm KB, Leontiadis GI, Ford AC, Ichinose M, Sugano K, Jeong M, Park JM, Han YM, Park KY, Lee DH, Yoo JH, Cho JY, Hahm KB, Bang CS, Baik GH, Shin IS, Kim JB, Suk KT, Yoon JH, Kim YS, Kim DJ * Helicobacter pylori Eradication for Prevention of Metachronous Recurrence after Endoscopic Resection of Early Gastric Cancer(140 visite) N Engl J Med (ISSN: 0028-4793, 0028-4793linking, 1533-4406electronic), 2015 Jun; 30642104201566393291: 749-756. Impact Factor:59.558 DettagliEsporta in BibTeXEsporta in EndNote
152 Records (130 escludendo Abstract e Conferenze). Impact factor totale: 664.847 (579.271 escludendo Abstract e Conferenze). Impact factor a 5 anni totale: 704.634 (607.994 escludendo Abstract e Conferenze).