Cancer Science Institute of Singapore, National University of Singapore, Republic of Singapore.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore.
Haematologica. 2020 Sep 1;105(9):2286-2297. doi: 10.3324/haematol.2019.230482.
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.
分化疗法在急性早幼粒细胞白血病（一种急性髓细胞白血病亚型）中取得了显著的成功。然而，除急性早幼粒细胞白血病外，分化疗法在急性髓细胞白血病中的临床获益可以忽略不计，除了突变型异柠檬酸脱氢酶 1/2 以外。二氢乳清酸脱氢酶催化从头嘧啶合成途径的第四步。ASLAN003 是一种高效的二氢乳清酸脱氢酶抑制剂，可诱导急性髓系白血病细胞系和原始急性髓系白血病细胞的分化，减少细胞增殖和活力，包括对化疗耐药的细胞。ASLAN003 触发凋亡途径，还显著抑制蛋白质合成并激活 AP-1 转录，有助于其促进分化的能力。最后，ASLAN003 可显著降低急性髓系白血病异种移植小鼠和急性髓系白血病患者来源异种移植模型中的白血病负担并延长其生存期。值得注意的是，该药物对正常造血细胞没有明显影响，并且在小鼠中表现出极好的安全性特征，即使在长时间给药后也是如此。因此，我们的研究结果表明 ASLAN003 是一种靶向二氢乳清酸脱氢酶的药物，具有治疗急性髓系白血病的潜力。ASLAN003 目前正在急性髓系白血病患者中进行 2a 期临床试验评估。
