Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Toutah, Krimo UNSPECIFIED UNSPECIFIED UNSPECIFIED Nawar, Nabanita UNSPECIFIED UNSPECIFIED UNSPECIFIED Timonen, Sanna UNSPECIFIED orcid.org/0000-0002-8139-5950 UNSPECIFIED Sorger, Helena UNSPECIFIED UNSPECIFIED UNSPECIFIED Raouf, Yasir S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bukhari, Shazreh UNSPECIFIED UNSPECIFIED UNSPECIFIED von Jan, Jana UNSPECIFIED UNSPECIFIED UNSPECIFIED Ianevski, Aleksandr UNSPECIFIED orcid.org/0000-0002-7780-482X UNSPECIFIED Gawel, Justyna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Olaoye, Olasunkanmi O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Geletu, Mulu UNSPECIFIED UNSPECIFIED UNSPECIFIED Abdeldayem, Ayah UNSPECIFIED UNSPECIFIED UNSPECIFIED Israelian, Johan UNSPECIFIED UNSPECIFIED UNSPECIFIED Radu, Tudor B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sedighi, Abootaleb UNSPECIFIED UNSPECIFIED UNSPECIFIED Bhatti, Muzaffar N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hassan, Muhammad Murtaza UNSPECIFIED UNSPECIFIED UNSPECIFIED Manaswiyoungkul, Pimyupa UNSPECIFIED UNSPECIFIED UNSPECIFIED Shouksmith, Andrew E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Neubauer, Heidi A. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Araujo, Elvin D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aittokallio, Tero UNSPECIFIED orcid.org/0000-0002-0886-9769 UNSPECIFIED Kraemer, Oliver H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Moriggl, Richard UNSPECIFIED orcid.org/0000-0003-0918-9463 UNSPECIFIED Mustjoki, Satu UNSPECIFIED orcid.org/0000-0002-0816-8241 UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Gunning, Patrick T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language HISTONE DEACETYLASE INHIBITOR; SUBEROYLANILIDE HYDROXAMIC ACID; ACCURATE DOCKING; BCL-2 INHIBITOR; TUBULIN; RICOLINOSTAT; COMBINATION; EXPRESSION; BORTEZOMIB; MODEL Multiple languages Chemistry, Medicinal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59959