In 2018, using a bioisosteric approach supported by structure based techniques, we discovered MEDS433, based on the 2-hydroxypyrazolo[1,5-a]pyridine scaffold. This compound shown to be an inhibitor of the human Dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis (IC50 = 1.2 nM), potent, on isolated protein, like the reference compound Brequinar. Moreover in the late 2016 the connection between Acute Myelogenous Leukemia (AML) and hDHODH, has attracted significant interest from pharmaceutical companies who have recognized it as a new therapeutic target for AML. So we tested MEDS433 in AML cell lines (THP1 and U937) and it was able to induce myeloid differentiation in the low nM range (EC50 = 40 and 26 nM) and show better qualities than brequinar (EC50 = 249 nM on THP1 and 189 nM on U937). These incredible in vitro results encouraged us to start the process of Drug Development on MEDS433; we have measured ADME properties and started in vivo pharmacokinetics and toxicity studies on mice as well as efficacy tests in different leukemic xenograft mouse models. In this occasion the MEDS433 profile is presented. The strategy that allowed the discovery of MEDS700, a metabolically stable MEDS433 backup compound is also presented.

Important steps into drug development of MEDS433, a potent human dihydroorotate dehydrogenase inhibitor based on the 2-hydroxypyrazolo[1,5-a]pyridine scaffold

Marta Giorgis
First
;
Stefano Sainas;Paola Circosta;Marilena Marraudino;Brigitta Bonaldo;Stefano Gotti;Chiara Vigato;Agnese Chiara Pippione;Donatella Boschi;Giuseppe Saglio;Marco Lucio Lolli
2022-01-01

Abstract

In 2018, using a bioisosteric approach supported by structure based techniques, we discovered MEDS433, based on the 2-hydroxypyrazolo[1,5-a]pyridine scaffold. This compound shown to be an inhibitor of the human Dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis (IC50 = 1.2 nM), potent, on isolated protein, like the reference compound Brequinar. Moreover in the late 2016 the connection between Acute Myelogenous Leukemia (AML) and hDHODH, has attracted significant interest from pharmaceutical companies who have recognized it as a new therapeutic target for AML. So we tested MEDS433 in AML cell lines (THP1 and U937) and it was able to induce myeloid differentiation in the low nM range (EC50 = 40 and 26 nM) and show better qualities than brequinar (EC50 = 249 nM on THP1 and 189 nM on U937). These incredible in vitro results encouraged us to start the process of Drug Development on MEDS433; we have measured ADME properties and started in vivo pharmacokinetics and toxicity studies on mice as well as efficacy tests in different leukemic xenograft mouse models. In this occasion the MEDS433 profile is presented. The strategy that allowed the discovery of MEDS700, a metabolically stable MEDS433 backup compound is also presented.
2022
12th JMMC – Joint Meeting on Medicinal Chemistry
Virtual Event
23- 26 November 2022
2th JMMC – Joint Meeting on Medicinal Chemistry
16
16
Marta Giorgis, Stefano Sainas, Paola Circosta, Alice Passoni, Renzo Bagnati, Marilena Marraudino, Brigitta Bonaldo, Stefano Gotti, Chiara Vigato, Agne...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1886273
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