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

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

  • J Med Chem. 2023 Jul 27;66(14):9954-9971. doi: 10.1021/acs.jmedchem.3c00788.
Kang Le 1,  Michael J Soth 1,  Jason B Cross 1,  Gang Liu 1,  William J Ray 2,  Jiacheng Ma 2,  Sunil G Goodwani 2,  Paul J Acton 2,  Virginie Buggia-Prevot 2,  Onno Akkermans 3,  John Barker 3,  Michael L Conner 1,  Yongying Jiang 1,  Zhen Liu 1,  Paul McEwan 3,  Jennifer Warner-Schmidt 4,  Alan Xu 1,  Matthias Zebisch 3,  Cobi J Heijnen 5 6,  Brett Abrahams 4,  Philip Jones 1
Affiliations

Affiliations

  • 1 Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • 2 Neurodegenerative Consortium (NDC), The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • 3 Evotec (UK) Ltd., Abingdon, OX14 4SA, UK.
  • 4 Alexandria Center for Life Science, Magnolia Neurosciences Corporation, New York, New York 10016, United States.
  • 5 Laboratories of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 6 Department of Psychological Sciences, Rice University, Houston, Texas 77005, United States.
PMID: 37436942 DOI: 10.1021/acs.jmedchem.3c00788
Abstract

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.

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