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Ferrata Storti Foundation
Haematologica 2020 Volume 105(9):2286-2297
Acute Myeloid Leukemia
ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia
Jianbiao Zhou,1,2 Jessie Yiying Quah,1* Yvonne Ng,1* Jing-Yuan Chooi,2* Sabrina Hui-Min Toh,1* Baohong Lin,3 Tuan Zea Tan,1 Hiroki Hosoi,1
Motomi Osato,1,4 Qihui Seet,5 A.G. Lisa Ooi,5 Bertil Lindmark,5 Mark McHale5 and Wee-Joo Chng1,2,3
1Cancer Science Institute of Singapore, National University of Singapore; 2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; 3Department of Hematology-Oncology, National University Cancer Institute, NUHS; 4Department of Pediatrics, National University of Singapore, Yong Loo Lin School of Medicine and 5ASLAN Pharmaceuticals, Singapore
*JYQ, YN, J-YC and SH-MT contributed equally to this work.
ABSTRACT
Differentiation therapies achieve remarkable success in acute promye- locytic leukemia, a subtype of acute myeloid leukemia (AML). However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies in AML are negligible except for those targeting mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase cat- alyzes the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reducing cell proliferation and viability, of AML cell lines and primary AML blasts including chemoresistant cells. Apoptotic pathways are triggered by ASLAN003, and this drug also signifi- cantly inhibits protein synthesis and activates AP-1 transcription, contribut- ing to its capacity to promote differentiation. Finally, ASLAN003 substantial- ly reduces leukemic burden and prolongs survival in AML xenograft mice and AML patient-derived xenograft models. Notably, the drug has no evi- dent effect on normal hematopoietic cells and exhibits excellent safety pro- files in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential for use in the treatment of AML. ASLAN003 is currently being evaluated in a phase IIa clinical trial in patients with AML.
Introduction
Acute myeloid leukemia (AML) cells originate from hematopoietic stem cells, but fail to differentiate into functional mature cells; instead, they are arrested at an early stage of differentiation.1-4 AML-M3 (according to the French-American-British classification), acute promyelocytic leukemia, is a unique subtype with a specific t(15;17) chromosomal translocation, resulting in the PML-RARA fusion gene.5 The introduction of all-trans retinoic acid, a vitamin A metabolite, and subsequently arsenic trioxide, transformed the clinical management of acute promyelocytic leukemia, turning a highly fatal disease into a definitively curable one that can be treated without the need for toxic chemotherapy.6,7
In contrast to their excellent effectiveness in acute promyelocytic leukemia, dif- ferentiation therapies have not been as effective in the other types of AML despite decades of intensive laboratory research and numerous clinical trials. The one exception to date is treatment targeting AML with mutated isocitrate dehydroge- nase (IDH) 1 or 2.8,9 Enasidenib, a selective, non-competitive inhibitor of IDH2, induces differentiation of AML cells through reducing the oncometabolite 2- hydroxyglutarate in mutated IDH2.10 Ivosidenib, an IDH1 inhibitor, also induces differentiation through a similar mechanism in mutated IDH1. The approval of
Correspondence:
WEE-JOO CHNG
mdccwj@nus.edu.sg
Received: June 22, 2019. Accepted: November 5, 2019. Pre-published: November 7, 2019.
doi:10.3324/haematol.2019.230482 ©2020 Ferrata Storti Foundation
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