Tadashi Honda, Research Professor
Director, Anti-inflammatory Research Laboratory at Institute of Chemical Biology and Drug Discovery
B.S., 1974, M.S., 1976, Ph.D., 1979, The University of Tokyo. Suntory Institute for Biomedical Research 1979–1991. Chief Senior Researcher, 1991–1995, Central Pharmaceutical Research Institute at Japan Tobacco Inc. Research Faculty [Research Associate Professor (2005)], 1995–2010, Dartmouth College. Research Professor, 2010–present, Stony Brook University.
Phone: (631) 632-7162
Drug discovery of new anti-inflammatory and cytoprotective agents as well as the new chemistry that is derived from their syntheses and modifications has been the primary objectives of Dr. Honda's research program.
Dr. Honda was involved in the discovery of anti-cancer drugs based on natural product models over the past two decades in Japan. Amongst several anti-cancer drug candidates that he invented during his pharmaceutical career, 2α-L-arabinopyranosyl-9-hydroxyellipticinium bromide (SUN4599) was evaluated in phase II clinical trials for the treatment of solid tumors, but failed due to hepatoxicity.
Dr. Honda has been engaged in the development of new anti-inflammatory and cytoprotective agents by modifications of naturally occurring pentacyclic triterpenoids at Dartmouth College over the past 15 years. Amongst these new semisynthetic triterpenoids, bardoxolone methyl (BARD), which potently activates the cytoprotective Keap1/Nrf2/ antioxidant response element (ARE) pathway, was expected to be the first in class drug for the treatment of diabetic nephropathy. In a multi–center, double–blind, placebo–controlled phase 2b clinical trial, patients treated with BARD experienced a significant increase in estimated glomerular filtration rate (eGFR), compared with no change in the placebo group. However, the phase 3 studies were halted due to the adverse side effects including mortality.
Mechanism studies suggest that BARD regulates various proteins regarding inflammation and carcinogenesis, including Keap1, IKKβ, and JAK1, to name a few, by reversible Michael addition between the nonenolizable cyanoenone in ring A of BARD and the SH groups of cysteine moieties on these proteins. On the basis of the information that essential pharmacophores are nonenolizable cyanoenones, Dr. Honda designed tricyclic compounds containing nonenolizable cyanoenones which give reversible Michael adduct with a SH group. It has been shown that they are also potent activators of the Keap1/Nrf2/ARE pathway. Among such synthetic tricycles, TBE-31 with an ethynyl group shows remarkable features in various in vitro and in vivo bioassays related to inflammation and carcinogenesis, which BARD does not. Thus, TBE-31 is expected to be a first in class therapeutic for the treatment of diabetic nephropathy as a back-up compound of BARD. His research group has already established an improved synthesis of TBE-31, which is suitable for a large scale production at low cost. The toxicological evaluation of TBE-31 has been started in collaboration with Dr. Dinkova-Kostova (University of Dundee) in the United Kingdom.
Novel monocyclic cyanoenones (MCEs), which are derived from rings A and C of TBE-31, display unique and interesting features with respect to reactivity (as Michael acceptors) and biological potency. In a preliminary set of MCEs, one of the most reactive Michael acceptor is MCE-1 but the addition is reversible. For induction of the phase 2 cytoprotective enzyme NQO1 in Hepa 1c1c murine hepatoma cells, MCE-1 demonstrates the highest potency (CD value: 22 nM). This high potency of MCE-1 is really striking because sulforaphane, a Keap1/Nrf2/ARE activator, which is widely used by many research groups worldwide and in many disease models related to inflammation and cancer, has a CD of 200 nM. Currently, Dr. Honda’s group is exploring entirely new anti-inflammatory and cytoprotective agents containing MCE-1 as a warhead in collaboration with Dr. James Bliska (Stony Brook University) and Dr. Dale Mierke (Dartmouth College).