The success of brequinar, one of the most potent human dihydroorotate dehydrogenase (hDHODH) inhibitors, to induce in vitro and in vivo differentiation in mouse acute myeloid leukaemia (AML)[1] models, encourages researches to design new hDHODH inhibitors. By applying innovative scaffold-hopping replacement to brequinar, we designed a first generation of hDHODH inhibitors presenting nM activity on the isolated hDHODH.[2] In this occasion, we are presenting a second generation able to reach the brequinar hDHODH potency. Compound 1 was found also able to restore the myeloid differentiation in leukaemia cell lines at concentrations one digit lower than brequinar. Theoretical design, modelling, synthesis, SAR, X-ray crystallographic data, biological assays, preliminary ADME and in vivo toxicity are here presented and discussed.

Development of Potent Human Dihydroorotate Dehydrogenase Inhibitors Able to Induces Myeloid Differentiation

Stefano Sainas;Agnese C. Pippione;BONANNI, DAVIDE;Marta Giorgis;Elisa Lupino;Enrico Giraudo;Paola Circosta;Valentina Gaidano;Alessandro Cignetti;Marco Piccinini;Giuseppe Saglio;AL KARADAGHI, SALAM;Donatella Boschi;Marco L. Lolli
2018

Abstract

The success of brequinar, one of the most potent human dihydroorotate dehydrogenase (hDHODH) inhibitors, to induce in vitro and in vivo differentiation in mouse acute myeloid leukaemia (AML)[1] models, encourages researches to design new hDHODH inhibitors. By applying innovative scaffold-hopping replacement to brequinar, we designed a first generation of hDHODH inhibitors presenting nM activity on the isolated hDHODH.[2] In this occasion, we are presenting a second generation able to reach the brequinar hDHODH potency. Compound 1 was found also able to restore the myeloid differentiation in leukaemia cell lines at concentrations one digit lower than brequinar. Theoretical design, modelling, synthesis, SAR, X-ray crystallographic data, biological assays, preliminary ADME and in vivo toxicity are here presented and discussed.
VII European Workshop Drug Synthesis
La Certosa di Pontignano, Siena
May 20 - 24, 2018
VII European Workshop Drug Synthesis
3
3
http://www.ewdsy.it/
Stefano Sainas, Agnese C. Pippione, Davide Bonanni, Marta Giorgis, Elisa Lupino, Enrico Giraudo, Paola Circosta, Valentina Gaidano, Alessandro Cignetti, Marco Piccinini, Giuseppe Saglio, Salam Al-Karadaghi, Donatella Boschi, Marco L. Lolli
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1669761
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