DHODH x HOXA9

更新于：2024-11-01

基本信息

关联

项与 DHODH x HOXA9 相关的药物

ML390

靶点

DHODH x HOXA9

作用机制

DHODH调节剂 [+1]

在研机构-

原研机构

Harvard University [+2]

在研适应症-

非在研适应症

成人急性髓性白血病

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 DHODH x HOXA9 相关的临床结果

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100 项与 DHODH x HOXA9 相关的转化医学

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0 项与 DHODH x HOXA9 相关的专利（医药）

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项与 DHODH x HOXA9 相关的文献（医药）

2016-12-08·ACS Medicinal Chemistry Letters3区 · 医学

Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia

3区 · 医学

Article

作者: Lewis, Timothy A. ; Rustiguel, Joane K. ; Muñoz, Benito ; Sykes, David B. ; Schreiber, Stuart L. ; Nonato, Maria Cristina ; Scadden, David T. ; Law, Jason M.

Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.

2016-09-01·Cell1区 · 生物学

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

1区 · 生物学

Article

作者: Janzer, Andreas ; Ferrara, Steven J ; Szekely, Brian A ; Clish, Clary B ; Stoeckigt, Detlef ; Mercier, François E ; Cobert, Julien M ; Haynes, Mark K ; Law, Jason M ; Bachand, Jacqueline ; Sklar, Larry A ; Mukherjee, Siddhartha ; Schreiber, Stuart L ; Maxcy, Katrina L ; Sadreyev, Ruslan I ; Wawer, Mathias J ; Jain, Esha ; Schajnovitz, Amir ; Waller, Anna ; Lee, Dongjun ; Kfoury, Youmna S ; Sykes, David B ; Pierce, Kerry A ; Lewis, Timothy A ; Eheim, Ashley L ; Tolliday, Nicola J ; Scadden, David T ; Kotz, Joanne D ; Meyer, Hanna ; Clemons, Paul A

While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.