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

Krimo Toutah; Nabanita Nawar; Sanna Timonen; Helena Sorger; Yasir S Raouf; Shazreh Bukhari; Jana von Jan; Aleksandr Ianevski; Justyna M Gawel; Olasunkanmi O Olaoye; Mulu Geletu; Ayah Abdeldayem; Johan Israelian; Tudor B Radu; Abootaleb Sedighi; Muzaffar N Bhatti; Muhammad Murtaza Hassan; Pimyupa Manaswiyoungkul; Andrew E Shouksmith; Heidi A Neubauer; Elvin D de Araujo; Tero Aittokallio; Oliver H Krämer; Richard Moriggl; Satu Mustjoki; Marco Herling; Patrick T Gunning

doi:10.1021/acs.jmedchem.1c00420

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. Epub 2021 Jun 8.

Authors

Krimo Toutah¹, Nabanita Nawar^{1

2}, Sanna Timonen^{3

4

5}, Helena Sorger⁶, Yasir S Raouf^{1

2}, Shazreh Bukhari^{1

2}, Jana von Jan^{7

8

9}, Aleksandr Ianevski⁵, Justyna M Gawel¹, Olasunkanmi O Olaoye^{1

2}, Mulu Geletu¹, Ayah Abdeldayem^{1

2}, Johan Israelian^{1

2}, Tudor B Radu^{1

2}, Abootaleb Sedighi¹, Muzaffar N Bhatti¹, Muhammad Murtaza Hassan^{1

2}, Pimyupa Manaswiyoungkul^{1

2}, Andrew E Shouksmith¹, Heidi A Neubauer⁶, Elvin D de Araujo¹⁰, Tero Aittokallio^{5

11

12}, Oliver H Krämer¹³, Richard Moriggl⁶, 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Bendamustine Hydrochloride / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Line, Tumor
Drug Synergism
Histone Deacetylase 6 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / pharmacokinetics
Histone Deacetylase Inhibitors / therapeutic use*
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / pharmacokinetics
Hydroxamic Acids / therapeutic use*
Leukemia, Prolymphocytic, T-Cell / drug therapy*
Male
Mice
Molecular Docking Simulation
Molecular Structure
Pyrrolidines / pharmacology
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology
Sulfonamides / therapeutic use*
para-Aminobenzoates / pharmacology

Substances

Antineoplastic Agents
Bridged Bicyclo Compounds, Heterocyclic
Histone Deacetylase Inhibitors
Hydroxamic Acids
Pyrrolidines
RG7388
Sulfonamides
para-Aminobenzoates
Bendamustine Hydrochloride
HDAC6 protein, human
Histone Deacetylase 6
venetoclax

Abstract

Publication types

MeSH terms

Substances

Grants and funding