Identification of inhibitors for neurodegenerative diseases targeting dual leucine zipper kinase through virtual screening and molecular dynamics simulations

Article

Author: Koirala, S. ; Samanta, S. ; Kar, P.

Neurodegenerative diseases lead to a gradual decline in cognitive and motor functions due to the progressive loss of neurons in the central nervous system. The role of dual leucine zipper kinase (DLK) in regulating stress responses and neuronal death pathways highlights its significance as a target against neurodegenerative diseases. The non-availability of FDA-approved drugs emphasizes a need to identify novel DLK-inhibitors. We screened NPAtlas (Natural products) and MedChemExpress (FDA-approved) libraries to identify potent ATP-competitive DLK inhibitors. ADMET analyses identified four compounds (two natural products and two FDA-approved) with favourable features. Subsequently, we performed molecular dynamics simulations to examine the binding-stability and ligand-induced conformational dynamics. Molecular mechanics Poisson Boltzmann surface area (MM-PBSA) calculations demonstrated CID139591660, dithranol, and danthron having greater affinity, while CID156581477 showed lower affinity than control sunitinib. PCA and network analysis results indicated structural and network alteration post-ligand binding. Furthermore, we identified an analogue of CID156581477 using the deep learning-based web server DeLA Drug which demonstrated a higher affinity than its parent compound and the control and identified several crucial interacting residues. Overall, our study provides significant theoretical guidance for designing potent novel DLK inhibitors and compounds that could emerge as promising drug candidates against DLK following laboratory validation.

27 Jul 2023·Journal of medicinal chemistryQ1 · MEDICINE

Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy.

Q1 · MEDICINE

Article

Author: Heijnen, Cobi J ; Goodwani, Sunil G ; Liu, Zhen ; Jiang, Yongying ; Liu, Gang ; Jones, Philip ; Cross, Jason B ; Ray, William J ; Warner-Schmidt, Jennifer ; Zebisch, Matthias ; Conner, Michael L ; McEwan, Paul ; Buggia-Prevot, Virginie ; Akkermans, Onno ; Le, Kang ; Acton, Paul J ; Soth, Michael J ; Abrahams, Brett ; Barker, John ; Xu, Alan ; Ma, Jiacheng

Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.

Journal of Medicinal Chemistry

Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy

Author: Cross, Jason B. ; Heijnen, Cobi J. ; Liu, Zhen ; Jiang, Yongying ; Ray, William J. ; Zebisch, Matthias ; Liu, Gang ; Ma, Jiacheng ; Soth, Michael J. ; Jones, Philip ; Conner, Michael L. ; Barker, John ; Le, Kang ; McEwan, Paul ; Acton, Paul J. ; Buggia-Prevot, Virginie ; Abrahams, Brett ; Goodwani, Sunil G. ; Warner-Schmidt, Jennifer ; Xu, Alan ; Akkermans, Onno

Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options.Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway-an active axon degeneration program that engages the dual leucine zipper kinase (DLK).DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiol. conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases.We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN.Lead compound IACS-52825 (22) showed strongly effective reversal of mech. allodynia in a mouse model of CIPN and was advanced into preclin. development.

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Indication	Highest Phase	Country/Location	Organization	Date
Peripheral Nervous System Diseases	Preclinical	United States	M.D. Anderson International España SA	12 Jul 2023
Peripheral Nervous System Diseases	Preclinical	United States	The University of Texas MD Anderson Cancer Center	12 Jul 2023

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