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

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.