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

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.

Generalized biomolecular modeling and design with RoseTTAFold All-Atom

“…(H) Three examples of successful predictions with low similarity to the training set. Shown from left to right are G protein-coupled S1P receptor (PDB ID 7EW1; seq ID 31%), complex of DLK bound to an inhibitor (PDB ID 8OUS; seq ID 39%), and a Renilla luciferase bound to an azacoelenterazine (non-native substrate; PDB ID 7QXR; seq ID 23%) (68)(69)(70). In (B), (F), and (G), boxplots cut off at 20 Å for clarity; the center line represents the median, box limits are upper and lower quartiles, and whiskers are minimum and maximum values.…”

ATF2 phosphorylation is essential for neuronal apoptosis, linking the DLK/LZK kinase cascade to JUN upregulation

“…Moreover, although DLK and LZK have been studied in mouse models, how these two proteins cooperate to regulate neuronal death in human neurons remains unknown. The DLK pathway has been recognized as a promising therapeuIc target for many neurodegeneraIve condiIons, prompIng the development of DLK inhibitors [8][9][10][11] . However, a clinical trial tesIng DLK inhibitors in ALS paIents was recently halted due to safety concerns 12 , highlighIng a pressing need to be/er understand the DLK/LZK pathway in human neurons and idenIfy alternate candidate targets.…”

Decarboxylative C–N Coupling of 2,2-Difluorobicyclo[1.1.1]pentane (BCP-F2) Building Blocks

“…Two examples are shown in Figure as BCP groups incorporated in bioactive compounds. Compound I was exemplified by Pfizer as an Hsp90 inhibitor analogue, and compound II (IACS-52825) was disclosed recently by scientists from the University of Texas MD Anderson Cancer Center as the lead DLK inhibitor advancing into preclinical development …”