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
(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).
(Less)
- author
- organization
- publishing date
- 2021-05
- 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
-
- pmid:33844533
- scopus:85102878882
- 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
- 2024-09-08 07:23:16
@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) > 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}}, }