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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 Biphenyl Moiety

Sainas, Stefano ; Giorgis, Marta ; Circosta, Paola ; Gaidano, Valentina ; Bonanni, Davide ; Pippione, Agnese C. ; Bagnati, Renzo ; Passoni, Alice ; Qiu, Yaqi and Cojocaru, Carina Florina , et al. (2021) In Journal of Medicinal Chemistry 64(9). p.5404-5428
Abstract

The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1, a potent hDHODH inhibitor (IC50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC50 = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class... (More)

The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1, a potent hDHODH inhibitor (IC50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC50 = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, 17 is characterized by higher potency in inducing myeloid differentiation (EC50 = 17.3 nM), strong proapoptotic properties (EC50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC30(Jurkat) > 100 μM).

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
64
issue
9
pages
25 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85102878882
  • pmid:33844533
ISSN
0022-2623
DOI
10.1021/acs.jmedchem.0c01549
language
English
LU publication?
yes
id
94b22255-73b0-410a-aa43-486e54decfe4
date added to LUP
2021-12-27 13:44:34
date last changed
2024-06-30 00:20:56
@article{94b22255-73b0-410a-aa43-486e54decfe4,
  abstract     = {{<p>The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1, a potent hDHODH inhibitor (IC50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC50 = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, 17 is characterized by higher potency in inducing myeloid differentiation (EC50 = 17.3 nM), strong proapoptotic properties (EC50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC30(Jurkat) &gt; 100 μM).</p>}},
  author       = {{Sainas, Stefano and Giorgis, Marta and Circosta, Paola and Gaidano, Valentina and Bonanni, Davide and Pippione, Agnese C. and Bagnati, Renzo and Passoni, Alice and Qiu, Yaqi and Cojocaru, Carina Florina and Canepa, Barbara and Bona, Alessandro and Rolando, Barbara and Mishina, Mariia and Ramondetti, Cristina and Buccinnà, Barbara and Piccinini, Marco and Houshmand, Mohammad and Cignetti, Alessandro and Giraudo, Enrico and Al-Karadaghi, Salam and Boschi, Donatella and Saglio, Giuseppe and Lolli, Marco L.}},
  issn         = {{0022-2623}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{5404--5428}},
  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 Biphenyl Moiety}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.0c01549}},
  doi          = {{10.1021/acs.jmedchem.0c01549}},
  volume       = {{64}},
  year         = {{2021}},
}