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
2018-01-01

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.
2018
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: https://hdl.handle.net/2318/1669761
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