European Journal of Medicinal Chemistry, volume 201, pages 112411
PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia
Justyna M Gawel
1
,
Andrew E. Shouksmith
1
,
Yasir S Raouf
2, 3
,
Nabanita Nawar
2, 3
,
Krimo Toutah
1
,
Shazreh Bukhari
2, 3
,
Pimyupa Manaswiyoungkul
2, 3
,
Olasunkanmi O Olaoye
2, 3
,
Johan Israelian
2, 3
,
Tudor B Radu
2, 3
,
Aaron D Cabral
2, 3
,
Diana Sina
2, 3
,
Abootaleb Sedighi
1
,
Elvin Dominic De Araujo
1
,
Patrick T. Gunning
4
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
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359, Mississauga Road, Mississauga, Ontario, L5L 1C6, Canada
|
4
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
|
Publication type: Journal Article
Publication date: 2020-09-01
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 6.7
ISSN: 02235234, 17683254
Organic Chemistry
Drug Discovery
General Medicine
Pharmacology
Abstract
Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α -tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC50 = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards – citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
Top-30
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Citations by publishers
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14
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14 publications, 48.28%
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2 publications, 6.9%
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1 publication, 3.45%
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1 publication, 3.45%
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Wiley
1 publication, 3.45%
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Springer Nature
1 publication, 3.45%
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Autonomous Non-profit Organization Editorial Board of the journal Uspekhi Khimii
1 publication, 3.45%
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- We do not take into account publications without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Gawel J. M. et al. PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia // European Journal of Medicinal Chemistry. 2020. Vol. 201. p. 112411.
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Gawel J. M., Shouksmith A. E., Raouf Y. S., Nawar N., Toutah K., Bukhari S., Manaswiyoungkul P., Olaoye O. O., Israelian J., Radu T. B., Cabral A. D., Sina D., Sedighi A., De Araujo E. D., Gunning P. T. PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia // European Journal of Medicinal Chemistry. 2020. Vol. 201. p. 112411.
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TY - JOUR
DO - 10.1016/j.ejmech.2020.112411
UR - https://doi.org/10.1016/j.ejmech.2020.112411
TI - PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia
T2 - European Journal of Medicinal Chemistry
AU - Gawel, Justyna M
AU - Shouksmith, Andrew E.
AU - Raouf, Yasir S
AU - Nawar, Nabanita
AU - Toutah, Krimo
AU - Bukhari, Shazreh
AU - Manaswiyoungkul, Pimyupa
AU - Olaoye, Olasunkanmi O
AU - Israelian, Johan
AU - Radu, Tudor B
AU - Cabral, Aaron D
AU - Sina, Diana
AU - Sedighi, Abootaleb
AU - De Araujo, Elvin Dominic
AU - Gunning, Patrick T.
PY - 2020
DA - 2020/09/01 00:00:00
PB - Elsevier
SP - 112411
VL - 201
SN - 0223-5234
SN - 1768-3254
ER -
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@article{2020_Gawel,
author = {Justyna M Gawel and Andrew E. Shouksmith and Yasir S Raouf and Nabanita Nawar and Krimo Toutah and Shazreh Bukhari and Pimyupa Manaswiyoungkul and Olasunkanmi O Olaoye and Johan Israelian and Tudor B Radu and Aaron D Cabral and Diana Sina and Abootaleb Sedighi and Elvin Dominic De Araujo and Patrick T. Gunning},
title = {PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia},
journal = {European Journal of Medicinal Chemistry},
year = {2020},
volume = {201},
publisher = {Elsevier},
month = {sep},
url = {https://doi.org/10.1016/j.ejmech.2020.112411},
pages = {112411},
doi = {10.1016/j.ejmech.2020.112411}
}