In acute myeloid leukaemia (AML), blasts lose their ability to differentiate into mature cells and undergo apoptosis. Accordingly, a proapoptotic and differentiating therapy (arsenic and all trans retinoic acid, ATRA) has dramatically improved survival in acute promyelocytic leukaemia; however, such combination therapy is not available for other AML subtypes. While, in 2016, inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme of the pyrimidine biosynthesis, was found to induce differentiation in several AML models. In fact, brequinar (BRQ) was utilized in vivo studies.1We are optimising hDHODH inhibitors to improve potency and drug-like proprieties. Moreover, we would like to evaluate how different parameters such as, pKa, LogD7.4 of different carboxylic acid bioisosteres can influence in vitro and in vivo studies. The main objective is to identify the best inhibitor suitable for use in in vivo studies on AML animal model. In this work we will present a new generation of hDHODH inhibitors able to reach the enzymatic BRQ inhibition potency levels. Our data showed that MEDS433, the best of two series, was found able to restore the myeloid differentiation in leukaemia cell lines (U937 and THP1) at concentrations one digit lower than those achieved in experiments with BRQ. Furthermore, we characterized MEDS433 with in vitro and in vivo experiments, showing that it had a significant pro-apoptotic effect in several AML and CML cell lines, which was at least partially independent from the differentiating effect.3,4 Furthermore, MEDS433 had a significant pro-apoptotic effect on several AML cell lines, but not on non-AML cell lines. Finally, our preliminary results from in vivo experiments showed that i) MEDS433 wasn’t toxic on Balb/c mice after 5 weeks of intraperitoneal administration at two different doses 10 and 25 mg/Kg and during acute toxicity experiment was not toxic ad dose of 1 g/Kg; ii) the half-life was limited to 3-4 hours and iii) MEDS433 had a good antileukemic activity (approximately 50% reduction of the tumour volume compared with control, after 18 days of treatment in THP1-xenograft models obtained from NSG mice). Theoretical design, modeling, synthesis, SAR, X-ray crystallographic data, biological assays, Drug-Like proprieties, pharmacokinetic studies and in vivo evaluations on AML models will be here presented and discussed.

A differentiating and apoptotic therapy for Acute Myeloid Leukaemia using MEDS433, a potent human Dihydroorotate Dehydrogenase inhibitor

Stefano Sainas;Paola Circosta;Marta Giorgis;Agnese Chiara Pippione;Marilena Marraudino;Mohammad Houshmand;Brigitta Bonaldo;Valentina Gaidano;Alessandro Cignetti;Stefano Gotti;Giuseppe Saglio;Donatella Boschi;Marco Lucio Lolli
2021

Abstract

In acute myeloid leukaemia (AML), blasts lose their ability to differentiate into mature cells and undergo apoptosis. Accordingly, a proapoptotic and differentiating therapy (arsenic and all trans retinoic acid, ATRA) has dramatically improved survival in acute promyelocytic leukaemia; however, such combination therapy is not available for other AML subtypes. While, in 2016, inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme of the pyrimidine biosynthesis, was found to induce differentiation in several AML models. In fact, brequinar (BRQ) was utilized in vivo studies.1We are optimising hDHODH inhibitors to improve potency and drug-like proprieties. Moreover, we would like to evaluate how different parameters such as, pKa, LogD7.4 of different carboxylic acid bioisosteres can influence in vitro and in vivo studies. The main objective is to identify the best inhibitor suitable for use in in vivo studies on AML animal model. In this work we will present a new generation of hDHODH inhibitors able to reach the enzymatic BRQ inhibition potency levels. Our data showed that MEDS433, the best of two series, was found able to restore the myeloid differentiation in leukaemia cell lines (U937 and THP1) at concentrations one digit lower than those achieved in experiments with BRQ. Furthermore, we characterized MEDS433 with in vitro and in vivo experiments, showing that it had a significant pro-apoptotic effect in several AML and CML cell lines, which was at least partially independent from the differentiating effect.3,4 Furthermore, MEDS433 had a significant pro-apoptotic effect on several AML cell lines, but not on non-AML cell lines. Finally, our preliminary results from in vivo experiments showed that i) MEDS433 wasn’t toxic on Balb/c mice after 5 weeks of intraperitoneal administration at two different doses 10 and 25 mg/Kg and during acute toxicity experiment was not toxic ad dose of 1 g/Kg; ii) the half-life was limited to 3-4 hours and iii) MEDS433 had a good antileukemic activity (approximately 50% reduction of the tumour volume compared with control, after 18 days of treatment in THP1-xenograft models obtained from NSG mice). Theoretical design, modeling, synthesis, SAR, X-ray crystallographic data, biological assays, Drug-Like proprieties, pharmacokinetic studies and in vivo evaluations on AML models will be here presented and discussed.
EFMC-ISMC 2021, XXVI EFMC International Symposium on Medicinal Chemistry
Virtual Event
29 Agosto - 2 Settembre, 2021
EFMC-ISMC 2021, XXVI EFMC International Symposium on Medicinal Chemistry
373
373
Stefano Sainas, Paola Circosta, Marta Giorgis, Agnese Chiara Pippione, Marilena Marraudino, Mohammad Houshmand, Brigitta Bonaldo, Valentina Gaidano, Alessandro Cignetti, Stefano Gotti, Giuseppe Saglio, Salam Al-Karadaghi, Donatella Boschi, Marco Lucio Lolli
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1852960
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