Yutaka Kanda's research while affiliated with Tokyo Institute of Technology and other places

... KW-2478 is a potent, intravenous (i.v.), non-ansamycin, nonpurine Hsp90 inhibitor that exhibits antitumour activity in preclinical in vitro and in vivo MM models (Nakashima et al, 2010). This antitumour activity in MM cells is retained in the presence of bone marrow stromal cells (Juliger et al, 2008), suggesting that KW-2478 overcomes the protective effect of the bone marrow microenvironment. The combination of KW-2478 and BTZ showed greater antitumour activity than either agent alone in preclinical MM models (Ishii et al, 2012). ...

... KW-2449, whose chemical structure is not yet disclosed, induces cell death in FLT3-ITD-positive cells and inhibits FLT3-ITD phosphorylation with an IC 50 of 144 nM (Shiotsu et al., , 2008Pratz et al., 2009). Targets in addition to FLT3 include c-KIT and Aurora (Pratz et al., 2009). ...

... KW-2450 (Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ, USA) is an investigational, orally active, dual IGF-1R/insulin receptor (IR) tyrosine kinase inhibitor. [22][23][24] We describe in vitro and in vivo preclinical studies of KW-2450 plus lapatinib and letrozole and a phase I trial of the triple combination in postmenopausal patients with advanced/metastatic hormone receptor-positive, HER2-positive breast cancer. ...

... The installation of the conspicuous 1,2-dithiolan-3-one motif had ultimately been mastered in an intramolecular format, requiring no less than 13 steps downstream of macrolactam formation; to this end, an extra steering C-atom had to be introduced and then excised (Scheme 1C). [13,21] This daunting issue notwithstanding, we opted against carrying an S-substituent through the sequence because of the many foreseeable incompatibilities of a thioether (or an equivalent thereof) with organometallic reagents and catalysts. Another aspect of critical importance to be considered at the outset was inferred from the unique mode of action of compounds of this type: formation of an episulfonium intermediate such as C mandates close transannular proximity between the reacting sites, which likely implies that ring strain is the trigger; [22,23] in this context, it is important to note that no less than 11 of the 18 atoms forming the macrocyclic envelope are sp 2 -hybridized. ...

... Leinamycin (3), a secondary metabolite isolated from the culture broth of the Streptomyces atroolivaceus S-140 strain, exhibits potent activity in vitro and in vivo even against tumors that are resistant to clinically approved anticancer drugs such as doxorubicin, cisplatin, cyclophosphamide or mitomycin. [1,2] This auspicious profile is deemed to result from a unique mode of action (Scheme 1). ...

... The installation of the conspicuous 1,2-dithiolan-3-one motif had ultimately been mastered in an intramolecular format, requiring no less than 13 steps downstream of macrolactam formation; to this end, an extra steering C-atom had to be introduced and then excised (Scheme 1C). [13,21] This daunting issue notwithstanding, we opted against carrying an S-substituent through the sequence because of the many foreseeable incompatibilities of a thioether (or an equivalent thereof) with organometallic reagents and catalysts. Another aspect of critical importance to be considered at the outset was inferred from the unique mode of action of compounds of this type: formation of an episulfonium intermediate such as C mandates close transannular proximity between the reacting sites, which likely implies that ring strain is the trigger; [22,23] in this context, it is important to note that no less than 11 of the 18 atoms forming the macrocyclic envelope are sp 2 -hybridized. ...

... Among the derivatives of GM, IPI-504 was identified as a prodrug of 17-AAG, specifically a hydroquinone hydrochloride formulation, exhibiting enhanced potency and improved toxicity profiles in preclinical investigations compared to its parent compound. Results from Phase 1 clinical trials indicated that KW-2478, used for multiple myeloma either independently or along with bortezomib, exhibited a positive response rate of 39% and a progression-free survival of 26.4 weeks [167]. The availability of X-ray crystallographic structures for HSP90 attached to ATP, geldanamycin, and radicicol has proved pivotal in formulating HSP90 inhibitors, ultimately contributing to the development of synthetic inhibitors. ...

... Among these drugs, KW-2449, has a potent and pronounced kinase inhibition profile against FLT3, ABL, ABL-T315I, and Aurora kinase. Based on a research, KW-2449 shows remarkable efficacy and should be clinically evaluated in patients with leukemia who have FLT3 mutations and/or mutations that are resistant to imatinib (Shiotsu et al. 2009). Inhibition of kinases that phosphorylate tau and amyloid precursor protein (APP) has been further explored as a treatment for Alzheimer's disease (reviewed in Bagheri and Saboury 2022). ...

... For measurement of apoptosis induction, caspase-3 like protease (DEVDase) activity was measured using the fluorogenic substrate acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspartic acid-7-amino-4-methylcoumarin (DEVD-AMC, Peptide Institute, Osaka, Japan), as described previously. 17 Determination of synergism by the combination index (CI) method ...

... triphenylphosphine)palladium(0) in the presence of triethylammonium formate as the allyl accepting nucleophile, according an N-alloc deprotection method successfully used by Kanda et al.[230] (see Scheme 2.59 below) ...