The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies
The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies
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DOI：
10.1038/s41375-019-0461-5
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发表时间：
2019-10-01
期刊：
影响因子：
11.4
通讯作者：
Janzer, Andreas
中科院分区：
文献类型：
--
作者：
Christian, Sven;Merz, Claudia;Janzer, Andreas
急性髓性白血病（AML）是一种毁灭性的疾病，大多数患者在诊断后一年内死亡。对于复发性/难治性AML患者，目前可用的治疗方法的预后特别差。虽然基因异质性，AML亚型共享一个共同的分化停滞在造血祖细胞阶段。克服这种分化停滞有可能改善患者的长期生存，如急性早幼粒细胞白血病（APL），其特征是涉及维甲酸受体α基因的染色体易位。全反式维甲酸（ATRA）治疗APL可诱导白血病早幼粒细胞终末分化和凋亡，治愈率达80%以上。不幸的是，迄今为止，在APL之外缺乏类似有效的分化疗法。二氢乳清酸脱氢酶（DHODH）是嘧啶从头合成途径中的关键酶，最近报道抑制DHODH可诱导不同AML亚型的分化。在这份报告中，我们描述了BAY 2402234的发现和表征-一种新型的，有效的，选择性的和口服生物可利用的DHODH抑制剂，显示出单一疗法的疗效和对多种AML亚型的分化诱导。在此，我们提出的临床前数据，导致启动的I期评价这种抑制剂在骨髓恶性肿瘤。
Acute myeloid leukemia (AML) is a devastating disease, with the majority of patients dying within a year of diagnosis. For patients with relapsed/refractory AML, the prognosis is particularly poor with currently available treatments. Although genetically heterogeneous, AML subtypes share a common differentiation arrest at hematopoietic progenitor stages. Overcoming this differentiation arrest has the potential to improve the long-term survival of patients, as is the case in acute promyelocytic leukemia (APL), which is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene. Treatment of APL with all-trans retinoic acid (ATRA) induces terminal differentiation and apoptosis of leukemic promyelocytes, resulting in cure rates of over 80%. Unfortunately, similarly efficacious differentiation therapies have, to date, been lacking outside of APL. Inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, was recently reported to induce differentiation of diverse AML subtypes. In this report we describe the discovery and characterization of BAY 2402234 - a novel, potent, selective and orally bioavailable DHODH inhibitor that shows monotherapy efficacy and differentiation induction across multiple AML subtypes. Herein, we present the preclinical data that led to initiation of a phase I evaluation of this inhibitor in myeloid malignancies.