@article{Jianbiao Zhou_Jessie Yiying Quah_Yvonne Ng_Jing-Yuan Chooi_Sabrina Hui-Min Toh_Baohong Lin_Tuan Zea Tan_Hiroki Hosoi_Motomi Osato_Qihui Seet_A.G. Lisa Ooi_Bertil Lindmark_Mark McHale_Wee-Joo Chng_2020, place={Pavia, Italy}, title={ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia}, volume={105}, url={https://haematologica.org/article/view/9559}, DOI={10.3324/haematol.2019.230482}, abstractNote={<p>Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reduces cell proliferation and viability, of acute myeloid leukemia cell lines and primary acute myeloid leukemia blasts including in chemo-resistant cells. Apoptotic pathways are triggered by ASLAN003, and it also significantly inhibits protein synthesis and activates AP-1 transcription, contributing to its differentiation promoting capacity. Finally, ASLAN003 substantially reduces leukemic burden and prolongs survival in acute myeloid leukemia xenograft mice and acute myeloid leukemia patient-derived xenograft models. Notably, the drug has no evident effect on normal hematopoietic cells and exhibits excellent safety profiles in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential in the treatment of acute myeloid leukemia. ASLAN003 is currently being evaluated in phase 2a clinical trial in acute myeloid leukemia patients.</p&gt;}, number={9}, journal={Haematologica}, author={Jianbiao Zhou and Jessie Yiying Quah and Yvonne Ng and Jing-Yuan Chooi and Sabrina Hui-Min Toh and Baohong Lin and Tuan Zea Tan and Hiroki Hosoi and Motomi Osato and Qihui Seet and A.G. Lisa Ooi and Bertil Lindmark and Mark McHale and Wee-Joo Chng}, year={2020}, month={Aug.}, pages={2286-2297} }