2. Academic Validation
  3. Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

  • J Med Chem. 2021 Jun 24;64(12):8486-8509. doi: 10.1021/acs.jmedchem.1c00420.
Krimo Toutah 1,  Nabanita Nawar 1 2,  Sanna Timonen 3 4 5,  Helena Sorger 6,  Yasir S Raouf 1 2,  Shazreh Bukhari 1 2,  Jana von Jan 7 8 9,  Aleksandr Ianevski 5,  Justyna M Gawel 1,  Olasunkanmi O Olaoye 1 2,  Mulu Geletu 1,  Ayah Abdeldayem 1 2,  Johan Israelian 1 2,  Tudor B Radu 1 2,  Abootaleb Sedighi 1,  Muzaffar N Bhatti 1,  Muhammad Murtaza Hassan 1 2,  Pimyupa Manaswiyoungkul 1 2,  Andrew E Shouksmith 1,  Heidi A Neubauer 6,  Elvin D de Araujo 10,  Tero Aittokallio 5 11 12,  Oliver H Krämer 13,  Richard Moriggl 6,  Satu Mustjoki 3 4 14,  Marco Herling 7 8 9,  Patrick T Gunning 1 2 10
Affiliations

Affiliations

  • 1 Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • 2 Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • 3 Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, 00029 HUS, Finland.
  • 4 Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, 00014 Helsinki, Finland.
  • 5 Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, 00014 Helsinki, Finland.
  • 6 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, A-1210 Vienna, Austria.
  • 7 Department of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf (CIO ABCD), University of Cologne (UoC), 50923 Cologne, Germany.
  • 8 Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), UoC, 50923 Cologne, Germany.
  • 9 Center for Molecular Medicine Cologne (CMMC), UoC, 50923 Cologne, Germany.
  • 10 Centre for Medicinal Chemistry, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
  • 11 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
  • 12 Oslo Centre for Biostatistics and Epidemiology, University of Oslo, 0316 Oslo, Norway.
  • 13 Department of Toxicology, University Medical Center, 55131 Mainz, Germany.
  • 14 iCAN Digital Precision Cancer Medicine Flagship, 00014 Helsinki, Finland.
PMID: 34101461 DOI: 10.1021/acs.jmedchem.1c00420
Abstract

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, where HDAC6 was 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-128436
    HDAC6抑制剂
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