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

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

Synthesis of pryridine and 2,2'-biprydine derivatives from the aza Diels-Alder reaction of substituted 1,2,4-triazines

Amidrazone 1a and the tricarbonyl derivatives 2b–d reacted in boiling ethanol in the presence of 2,5-norbornadiene 5 giving the pyridine derivatives 6b–d respectively (59–72%) and in the presence of 2,3-dihydrofuran 7 yielding the lactones 10b–d (39–44%). The 2,2′-bipyridine derivatives 6e–g were similarly obtained in good yield (81–87%) from the reaction of amidrazone 1b and tricarbonyl derivatives 2b–d in the presence of 2,5-norbornadiene 5

Synthesis of pyridine derivatives using aza Diels-Alder methodology

Amidrazone 1 reacted with the unsymmetrical tricarbonyls 2a, 2c and 2d giving triazines 3a, 3c and 3d, respectively. These triazines were converted into their corresponding pyridine derivatives 6a, 6c and 6d in aza Diels-Alder reactions with 2,5-norbornadiene 5. Triazines 3c and 3d gave the pyridolactones 9c and 9d with 2,3-dihydrofuran

Synthesis of 2,2′-bipyridyl derivatives using aza Diels-Alder methodology

Amidrazone 1 and the tricarbonyl derivatives 2a-c gave the triazines 3a-c, respectively, which reacted with 2,5-norbornadiene 4 in boiling ethanol yielding the corresponding novel 2,2′-bipyridines 5a-c in good yield. Triazine 6 gave the 2,2′-bipyridyl derivative 7 (65%) with compound 4 in 1,2-dichlorobenzene at 140°C. © 2003 Elsevier Science Ltd. All rights reserved

Arylated pyridines: Suzuki reactions of O-substituted 2,6-dihalogenated-3-hydroxypyridines

2-Bromo-6-iodo-3-methoxypyridine 5b yielded mono-arylated derivatives 6b-9b and teraryls 10b-14b in selective Suzuki reactions