Human dihydroorotate dehydrogenase (hDHODH) catalyses the fourth step in the de novo pyrimidine biosynthesis where dihydroorotate (DHO) is converted to orotate (ORO).(1) Being already validated as therapeutic target for the treatment of autoimmune diseases, as rheumatoid arthritis or multiple sclerosis,(2) quite recently hDHODH was associated to acute myeloid leukaemia (AML),(3) a disease where the standard of intensive care has not changed in the last four decades.(4) The success of brequinar (Figure 1), one of the most potent known hDHODH inhibitors, to induce in vitro and in vivo differentiation in mouse AML models,(3) highly encourages researches to design hDHODH inhibitors with better drug-like profiles. Starting from brequinar, by applying innovative scaffold-hopping replacement, we recently designed a first generation of potent hDHODH inhibitors presenting nM activity on the isolated hDHODH.(5) Following that early affords, in this occasion we are presenting a second generation of inhibitors (Figure 1) able to reach the brequinar hDHODH potency levels. Compound 1, the best of two series, was found able to restore the myeloid differentiation in leukaemia cell lines (U937 and THP-1) at concentrations one digit lower than those achieved in experiments with brequinar. Theoretical design, modeling, synthesis, SAR, X-ray crystallographic data, biological assays, preliminary ADME and in vivo toxicity are here presented and discussed.

In vitro myeloid differentiation using a new generation of potent human dihydroorotate dehydrogenase (hDHODH) inhibitors

Sainas Stefano;Pippione Agnese Chiara;Bonanni Davide;Giorgis Marta;Lupino Elisa;Giraudo Enrico;Circosta Paola;Gaidano Valentina;Cignetti Alessandro;Piccinini Marco;Saglio Giuseppe;Al-Karadaghi Salam;Boschi Donatella;Lolli Marco Lucio
2018-01-01

Abstract

Human dihydroorotate dehydrogenase (hDHODH) catalyses the fourth step in the de novo pyrimidine biosynthesis where dihydroorotate (DHO) is converted to orotate (ORO).(1) Being already validated as therapeutic target for the treatment of autoimmune diseases, as rheumatoid arthritis or multiple sclerosis,(2) quite recently hDHODH was associated to acute myeloid leukaemia (AML),(3) a disease where the standard of intensive care has not changed in the last four decades.(4) The success of brequinar (Figure 1), one of the most potent known hDHODH inhibitors, to induce in vitro and in vivo differentiation in mouse AML models,(3) highly encourages researches to design hDHODH inhibitors with better drug-like profiles. Starting from brequinar, by applying innovative scaffold-hopping replacement, we recently designed a first generation of potent hDHODH inhibitors presenting nM activity on the isolated hDHODH.(5) Following that early affords, in this occasion we are presenting a second generation of inhibitors (Figure 1) able to reach the brequinar hDHODH potency levels. Compound 1, the best of two series, was found able to restore the myeloid differentiation in leukaemia cell lines (U937 and THP-1) at concentrations one digit lower than those achieved in experiments with brequinar. Theoretical design, modeling, synthesis, SAR, X-ray crystallographic data, biological assays, preliminary ADME and in vivo toxicity are here presented and discussed.
2018
Italian-Spanish-Portuguese Joint Meeting in Medicinal Chemistry MedChemSicily2018
Palermo
July 17-20, 2018
Italian - Spanish - Portuguese Joint Meeting in Medicinal Chemistry MedChemSicily2018
1
244
https://www.medchemsicily2018.it/
Sainas Stefano, Pippione Agnese Chiara, Bonanni Davide, Giorgis Marta, Lupino Elisa, Giraudo Enrico, Goyal Parveen, Circosta Paola, Gaidano Valentina,...espandi
File in questo prodotto:
File Dimensione Formato  
book_of_abstracts.pdf

Accesso riservato

Descrizione: Book of Abstract
Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 37.91 MB
Formato Adobe PDF
37.91 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Invited_Oral_Sainas.pdf

Accesso riservato

Descrizione: Abstract
Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 129.48 kB
Formato Adobe PDF
129.48 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1677690
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact