591249-21-7Relevant articles and documents
Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia
Toutah, Krimo,Nawar, Nabanita,Timonen, Sanna,Sorger, Helena,Raouf, Yasir S.,Bukhari, Shazreh,von Jan, Jana,Ianevski, Aleksandr,Gawel, Justyna M.,Olaoye, Olasunkanmi O.,Geletu, Mulu,Abdeldayem, Ayah,Israelian, Johan,Radu, Tudor B.,Sedighi, Abootaleb,Bhatti, Muzaffar N.,Hassan, Muhammad Murtaza,Manaswiyoungkul, Pimyupa,Shouksmith, Andrew E.,Neubauer, Heidi A.,de Araujo, Elvin D.,Aittokallio, Tero,Kr?mer, Oliver H.,Moriggl, Richard,Mustjoki, Satu,Herling, Marco,Gunning, Patrick T.
, p. 8486 - 8509 (2021)
Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, whereHDAC6was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as stand-alone or in combination with targeted drugs.
Nucleophilic Aromatic Substitution in Hydrodefluorination Exemplified by Hydridoiridium(III) Complexes with Fluorinated Phenylsulfonyl-1,2-diphenylethylenediamine Ligands
Matsunami, Asuka,Kayaki, Yoshihito,Kuwata, Shigeki,Ikariya, Takao
, p. 1958 - 1969 (2018)
In connection with the mechanism of the catalytic reduction of fluoroarenes, the intramolecular defluorinative transformation of a family of iridium hydrides utilized as a hydrogen transfer catalyst is studied. Hydridoiridium(III) complexes bearing fluorinated phenylsulfonyl-1,2-diphenylethylenediamine ligands are spontaneously converted into iridacycles via selective C-F bond cleavage at the ortho position. NMR spectroscopic studies and synthesis of intermediate model compounds verify the stepwise pathway involving intramolecular substitution of the ortho-fluorine atom by the hydrido ligand, i.e., hydrodefluorination (HDF), and the following fluoride-assisted cyclometalation at the transiently formed C-H bond. A hydridoiridium complex with a 2,3,4,5,6-pentafluorophenylsulfonyl (Fs) substituent is more susceptible to HDF than its analog with a 2,3,4,5-tetrafluorophenylsulfonyl (FsH) group. The FsH-derivative clearly shows that C-F bond cleavage occurs in preference to C-H activation. These experimental results firmly support the nucleophilic aromatic substitution (SNAr) mechanism in HDF by hydridoiridium species.
