Toutah, Krimo, Nawar, Nabanita, Timonen, Sanna ORCID: 0000-0002-8139-5950, Sorger, Helena, Raouf, Yasir S., Bukhari, Shazreh, von Jan, Jana, Ianevski, Aleksandr ORCID: 0000-0002-7780-482X, 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 ORCID: 0000-0002-0886-9769, Kraemer, Oliver H., Moriggl, Richard ORCID: 0000-0003-0918-9463, Mustjoki, Satu ORCID: 0000-0002-0816-8241, Herling, Marco and Gunning, Patrick T. (2021). Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia. J. Med. Chem., 64 (12). S. 8486 - 8510. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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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 standalone or in combination with targeted drugs.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Toutah, KrimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nawar, NabanitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Timonen, SannaUNSPECIFIEDorcid.org/0000-0002-8139-5950UNSPECIFIED
Sorger, HelenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raouf, Yasir S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bukhari, ShazrehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Jan, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ianevski, AleksandrUNSPECIFIEDorcid.org/0000-0002-7780-482XUNSPECIFIED
Gawel, Justyna M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olaoye, Olasunkanmi O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geletu, MuluUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdeldayem, AyahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Israelian, JohanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radu, Tudor B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sedighi, AbootalebUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bhatti, Muzaffar N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hassan, Muhammad MurtazaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manaswiyoungkul, PimyupaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shouksmith, Andrew E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neubauer, Heidi A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Araujo, Elvin D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aittokallio, TeroUNSPECIFIEDorcid.org/0000-0002-0886-9769UNSPECIFIED
Kraemer, Oliver H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moriggl, RichardUNSPECIFIEDorcid.org/0000-0003-0918-9463UNSPECIFIED
Mustjoki, SatuUNSPECIFIEDorcid.org/0000-0002-0816-8241UNSPECIFIED
Herling, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gunning, Patrick T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-599597
DOI: 10.1021/acs.jmedchem.1c00420
Journal or Publication Title: J. Med. Chem.
Volume: 64
Number: 12
Page Range: S. 8486 - 8510
Date: 2021
Publisher: AMER CHEMICAL SOC
Place of Publication: WASHINGTON
ISSN: 1520-4804
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HISTONE DEACETYLASE INHIBITOR; SUBEROYLANILIDE HYDROXAMIC ACID; ACCURATE DOCKING; BCL-2 INHIBITOR; TUBULIN; RICOLINOSTAT; COMBINATION; EXPRESSION; BORTEZOMIB; MODELMultiple languages
Chemistry, MedicinalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59959

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