更新于：2024-11-01

MAP3K13 x MAP3K12

更新于：2024-11-01

基本信息

关联

项与 MAP3K13 x MAP3K12 相关的药物

DN-1289

靶点

MAP3K12 x MAP3K13

作用机制

MAP3K12抑制剂 [+1]

在研机构

Denali Therapeutics, Inc.

原研机构

Denali Therapeutics, Inc.

在研适应症

肌萎缩侧索硬化

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MAP3K13 x MAP3K12 相关的临床结果

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100 项与 MAP3K13 x MAP3K12 相关的转化医学

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0 项与 MAP3K13 x MAP3K12 相关的专利（医药）

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项与 MAP3K13 x MAP3K12 相关的文献（医药）

2022-12-22·Journal of Medicinal Chemistry1区 · 医学

Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis

1区 · 医学

Article

作者: de Vicente, Javier ; Scearce-Levie, Kimberly ; Kane, Lesley A. ; Fox, Brian M. ; Solanoy, Hilda ; Srivastava, Ankita ; Rana, Anil ; Xu, Musheng ; Lei, Yanan ; Sweeney, Zachary K. ; Craig, Robert A. ; Poda, Suresh B. ; Earr, Timothy ; Fleck, Daniel ; Haddick, Patrick C. G. ; Zhuo, Zheng ; Kajiwara, Yuji ; Wang, Jing ; Takahashi, Ryan H. ; Osipov, Maksim ; Canet, Mark J. ; Chau, Roni ; Lexa, Katrina W. ; Thottumkara, Arun P. ; Tong, Vincent ; Larhammar, Martin ; Yulyaningsih, Ernie ; Lucas, Anthony ; Nguyen, Hoang ; Miyamoto, Takashi ; Zhang, Rui ; Hu, Cheng ; He, Jianrong

Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (14), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis.

2022-08-10·The Journal of Neuroscience

The MAP3Ks DLK and LZK Direct Diverse Responses to Axon Damage in Zebrafish Peripheral Neurons

Article

作者: Rolls, Melissa M ; Shorey, Matthew ; Chen, Shu-Fan ; Chauhan, Vasudha ; Sagasti, Alvaro ; Nassman, Khaled ; Adula, Kadidia Pemba

Mitogen-activated protein kinase kinase kinases (MAP3Ks) dual leucine kinase (DLK) and leucine zipper kinase (LZK) are essential mediators of axon damage responses, but their responses are varied, complex, and incompletely understood. To characterize their functions in axon injury, we generated zebrafish mutants of each gene, labeled motor neurons (MNs) and touch-sensing neurons in live zebrafish, precisely cut their axons with a laser, and assessed the ability of mutant axons to regenerate in larvae, before sex is apparent in zebrafish. DLK and LZK were required redundantly and cell autonomously for axon regeneration in MNs but not in larval Rohon-Beard (RB) or adult dorsal root ganglion (DRG) sensory neurons. Surprisingly, in dlk lzk double mutants, the spared branches of wounded RB axons grew excessively, suggesting that these kinases inhibit regenerative sprouting in damaged axons. Uninjured trigeminal sensory axons also grew excessively in mutants when neighboring neurons were ablated, indicating that these MAP3Ks are general inhibitors of sensory axon growth. These results demonstrate that zebrafish DLK and LZK promote diverse injury responses, depending on the neuronal cell identity and type of axonal injury.SIGNIFICANCE STATEMENT The MAP3Ks DLK and LZK are damage sensors that promote diverse outcomes to neuronal injury, including axon regeneration. Understanding their context-specific functions is a prerequisite to considering these kinases as therapeutic targets. To investigate DLK and LZK cell-type-specific functions, we created zebrafish mutants in each gene. Using mosaic cell labeling and precise laser injury we found that both proteins were required for axon regeneration in motor neurons but, unexpectedly, were not required for axon regeneration in Rohon-Beard or DRG sensory neurons and negatively regulated sprouting in the spared axons of touch-sensing neurons. These findings emphasize that animals have evolved distinct mechanisms to regulate injury site regeneration and collateral sprouting, and identify differential roles for DLK and LZK in these processes.

2022-05-04·The Journal of Neuroscience

A Critical Role for DLK and LZK in Axonal Repair in the Mammalian Spinal Cord

Article

作者: Tsai, Kristen M ; Kim, Hugo J ; Smadi, Samraa ; Allibhoy, Sahar ; Kim, Noah D ; Zheng, Binhai ; Romaus-Sanjurjo, Daniel ; Saikia, Junmi M ; Simonyan, Lidiya ; Chavez-Martinez, Carmine L ; Jin, Yishi

The limited ability for axonal repair after spinal cord injury underlies long-term functional impairment. Dual leucine-zipper kinase [DLK; MAP kinase kinase kinase 12; MAP3K12] is an evolutionarily conserved MAP3K implicated in neuronal injury signaling fromCaenorhabditis elegansto mammals. However, whether DLK or its close homolog leucine zipper kinase (LZK; MAP3K13) regulates axonal repair in the mammalian spinal cord remains unknown. Here, we assess the role of endogenous DLK and LZK in the regeneration and compensatory sprouting of corticospinal tract (CST) axons in mice of both sexes with genetic analyses in a regeneration competent background provided by PTEN deletion. We found that inducible neuronal deletion of both DLK and LZK, but not either kinase alone, abolishes PTEN deletion-induced regeneration and sprouting of CST axons, and reduces naturally-occurring axon sprouting after injury. Thus, DLK/LZK-mediated injury signaling operates not only in injured neurons to regulate regeneration, but also unexpectedly in uninjured neurons to regulate sprouting. Deleting DLK and LZK does not interfere with PTEN/mTOR signaling, indicating that injury signaling and regenerative competence are independently controlled. Together with our previous study implicating LZK in astrocytic reactivity and scar formation, these data illustrate the multicellular function of this pair of MAP3Ks in both neurons and glia in the injury response of the mammalian spinal cord.SIGNIFICANCE STATEMENTFunctional recovery after spinal cord injury is limited because of a lack of axonal repair in the mammalian CNS. Dual leucine-zipper kinase (DLK) and leucine zipper kinase (LZK) are two closely related protein kinases that have emerged as regulators of neuronal responses to injury. However, their role in axonal repair in the mammalian spinal cord has not been described. Here, we show that DLK and LZK together play critical roles in axonal repair in the mammalian spinal cord, validating them as potential targets to promote repair and recovery after spinal cord injury. In addition to regulating axonal regeneration from injured neurons, both kinases also regulate compensatory axonal growth from uninjured neurons, indicating a more pervasive role in CNS repair than originally anticipated.