Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a major unmet medical need in which cancer patients on chemotherapy develop pain and/or loss of sensation in their extremities. Currently there is no effective treatment for prevention or reversal of CIPN. While the exact mechanisms underlying CIPN are debated, it is thought that the active axon degeneration program, which involves activation of the dual leucine zipper kinase (DLK, or MAP3K12), is engaged following chemotherapy and contributes to CIPN.  We have found that inhibitors of DLK protect against axonal degeneration of sensory neurons and prevent or reverse the effects of cisplatin in mouse models of CIPN.<br/>In this talk we will present the discovery and preclinical development of IACS-52825, a potent and selective DLK inhibitor containing a novel bicyclo[1.1.1]pentylimidazole core. We optimized potency of the series using structure-based drug design through displacement of a water and introduction of multiple multipolar interactions, and then fine-tuned metabolic stability with a strategically placed fluorine. IACS-52825 showed strong efficacy in mice reversing cisplatin-induced allodynia, and generally excellent properties supporting development as a preclinical candidate. We carried IACS-52825 through IND-enabling studies and eventually discontinued its development because of concerns surrounding an ocular toxicity upon chronic dosing in non-human primates.

Discovery and preclinical development of IACS-52825, a potent and selective DLK inhibitor for the treatment of chemotherapy-induced peripheral neuropathy

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.