8OUT

CRYSTAL STRUCTURE OF DLK IN COMPLEX WITH COMPOUND 22

Summary for 8OUT

• Entry DOI: 10.2210/pdb8out/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase 12, (1R)-1-[4-[6-azanyl-5-(trifluoromethyloxy)pyridin-3-yl]-1-(3-fluoranyl-1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2,2,2-tris(fluoranyl)ethanol (3 entities in total)
• Functional Keywords: dlk, kinase, inhibitor, signaling protein, transferase-inhibitor, m3k12
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34444.32

Authors

Zebisch, M.,Akkermans, O.,Barker, J.J.,Cross, J.B. (deposition date: 2023-04-24, release date: 2023-07-26, Last modification date: 2024-06-19)

Primary citation

Le, K.,Soth, M.J.,Cross, J.B.,Liu, G.,Ray, W.J.,Ma, J.,Goodwani, S.G.,Acton, P.J.,Buggia-Prevot, V.,Akkermans, O.,Barker, J.,Conner, M.L.,Jiang, Y.,Liu, Z.,McEwan, P.,Warner-Schmidt, J.,Xu, A.,Zebisch, M.,Heijnen, C.J.,Abrahams, B.,Jones, P.
Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy.
J.Med.Chem., 66:9954-9971, 2023

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

PubMed: 37436942
DOI: 10.1021/acs.jmedchem.3c00788

Experimental method

X-RAY DIFFRACTION (1.935 Å)