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

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-128436

KT-531

HDAC6 Inhibitor

HDAC

Cancer

Name
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