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Papers of the Week

Papers: 8 Jul 2023 - 14 Jul 2023

Basic Science

Animal Studies, In Vitro Studies, Molecular/Cellular, Neurobiology, Pharmacology/Drug Development

Cancer Pain, Neuropathic Pain

2023 Jul 12

J Med Chem


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


Le K, Soth MJ, Cross JB, Liu G, Ray WJ, Ma J, Goodwani SG, Acton PJ, Buggia-Prevot V, Akkermans O, Barker J, Conner ML, Jiang Y, Liu Z, McEwan P, Warner-Schmidt J, Xu A, Zebisch M, Heijnen CJ, Abrahams B, Jones P


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 () showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.