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

• Published in: Journal of medicinal chemistry Vol. 66; no. 14; pp. 9954 - 9971
• Main Authors: Le, Kang, Soth, Michael J., Cross, Jason B., Liu, Gang, Ray, William J., Ma, Jiacheng, Goodwani, Sunil G., Acton, Paul J., Buggia-Prevot, Virginie, Akkermans, Onno, Barker, John, Conner, Michael L., Jiang, Yongying, Liu, Zhen, McEwan, Paul, Warner-Schmidt, Jennifer, Xu, Alan, Zebisch, Matthias, Heijnen, Cobi J., Abrahams, Brett, Jones, Philip
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.07.2023; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; LEUCINE-ZIPPER KINASE; DEGENERATION; MAP3K12
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00788

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.