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Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold : SAR of the Aryloxyaryl Moiety

Sainas, Stefano ; Giorgis, Marta ; Circosta, Paola ; Poli, Giulio ; Alberti, Marta ; Passoni, Alice ; Gaidano, Valentina ; Pippione, Agnese C. ; Vitale, Nicoletta and Bonanni, Davide , et al. (2022) In Journal of Medicinal Chemistry 65(19). p.12701-12724
Abstract

In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound... (More)

In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
65
issue
19
pages
24 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85139185177
  • pmid:36162075
ISSN
0022-2623
DOI
10.1021/acs.jmedchem.2c00496
language
English
LU publication?
yes
id
e142711d-fa33-49d2-980b-2e3ebb457041
date added to LUP
2022-12-14 13:14:17
date last changed
2024-06-24 20:40:31
@article{e142711d-fa33-49d2-980b-2e3ebb457041,
  abstract     = {{<p>In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.</p>}},
  author       = {{Sainas, Stefano and Giorgis, Marta and Circosta, Paola and Poli, Giulio and Alberti, Marta and Passoni, Alice and Gaidano, Valentina and Pippione, Agnese C. and Vitale, Nicoletta and Bonanni, Davide and Rolando, Barbara and Cignetti, Alessandro and Ramondetti, Cristina and Lanno, Alessia and Ferraris, Davide M. and Canepa, Barbara and Buccinnà, Barbara and Piccinini, Marco and Rizzi, Menico and Saglio, Giuseppe and Al-Karadaghi, Salam and Boschi, Donatella and Miggiano, Riccardo and Tuccinardi, Tiziano and Lolli, Marco L.}},
  issn         = {{0022-2623}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{19}},
  pages        = {{12701--12724}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold : SAR of the Aryloxyaryl Moiety}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.2c00496}},
  doi          = {{10.1021/acs.jmedchem.2c00496}},
  volume       = {{65}},
  year         = {{2022}},
}