Delving into the Latest Updates on CZC-25146 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

LRRK2

Mechanism

LRRK2 inhibitors(Leucine-rich repeat serine/threonine-protein kinase 2 inhibitors)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic Disease

Active Indication

Parkinson Disease

Inactive Indication-

Originator Organization

Cellzome AG

Active Organization

Cellzome AG

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC22H25FN6O4S

InChIKeyXXHHOTZUJIXPJX-UHFFFAOYSA-N

CAS Registry1191911-26-8

Author: Segal, Joe ; Greer, Cindy ; Ebner, Daniel ; Sahdeo, Sunil ; Danovi, Davide ; Rashid, S. Tamir ; Ng, Soon Seng ; Blackford, Samuel J.I. ; Ronzoni, Riccardo ; Irving, James A. ; Chowdary, Vivek ; Mueller, Christian ; Kent, Deniz ; Im, Yu Ri ; Syanda, Adam M. ; Li, Chao Zheng ; Khoshkenar, Payam ; Ismaili, Taylor ; Hatch, Stephanie ; Zieger, Marina ; Lomas, David A. ; Lewis, Patrick A.

Background:Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by the inheritance of the serpin family A member 1 “Z” genetic variant driving alpha-1 antitrypsin (AAT) protein misfolding in hepatocytes. There are no approved medicines for this disease.Methods:We conducted a high-throughput image-based small molecule screen using patient-derived induced pluripotent stem cell-hepatocytes (iPSC-hepatocytes). Identified targets were validated in vitro using 3 independent patient iPSC lines. The effects of the identified target, leucine-rich repeat kinase 2 (LRRK2), were further evaluated in an animal model of A1ATD through histology and immunohistochemistry and in an autophagy-reporter line. Autophagy induction was assessed through immunoblot and immunofluorescence analyses.Results:Small-molecule screen performed in iPSC-hepatocytes identified LRRK2 as a potentially new therapeutic target. Of the commercially available LRRK2 inhibitors tested, we identified CZC-25146, a candidate with favorable pharmacokinetic properties, as capable of reducing polymer load, increasing normal AAT secretion, and reducing inflammatory cytokines in both cells and PiZ mice. Mechanistically, this effect was achieved through the induction of autophagy.Conclusions:Our findings support the use of CZC-25146 and leucine-rich repeat kinase-2 inhibitors in hepatic proteinopathy research and their further investigation as novel therapeutic candidates for A1ATD.

100 Deals associated with CZC-25146

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