Delving into the Latest Updates on WRN Inhibitor(Eikon) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

WRN

Mechanism

WRN inhibitors(WRN RecQ like helicase inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Eikon Therapeutics, Inc.Startup

Active Organization

Eikon Therapeutics, Inc.Startup

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Miller, Rand M ; Butler, Renee ; McSwiggen, David ; Zhang, Zhengjian ; Anderson, Daniel ; Schiff, Lauren ; Bashore, Charlene ; Gonzalez, Eric ; Cheng, Kylie ; Kelly, Marcus ; Filbin, John ; Morrison, Huntly ; Ortega, Jose ; Loo, Mandy ; Heckert, Alec ; Tao, Arnold ; Tang, Yangzhong ; Rodríguez Pérez, Fernando ; Natwick, Dean ; Murnock, Danny ; Ho, Jaclyn ; Huey, Melina ; Van Buren, Kayla ; Tarvestad, William ; Basham, Stephen ; Miranda, Rafael G

AbstractSynthetic lethality provides an attractive strategy for developing targeted cancer therapies. For example, cancer cells with high levels of microsatellite instability (MSI-H) are dependent on the Werner (WRN) helicase for survival. However, the mechanisms that regulate WRN spatiotemporal dynamics remain poorly understood. Here, we used single-molecule tracking (SMT) in combination with a WRN inhibitor to examine WRN dynamics within the nuclei of living cancer cells. WRN inhibition traps the helicase on chromatin, requiring p97/VCP for extraction and proteasomal degradation in a MSI-H dependent manner. Using a phenotypic screen, we identify the PIAS4-RNF4 axis as the pathway responsible for WRN degradation. Finally, we show that co-inhibition of WRN and SUMOylation has an additive toxic effect in MSI-H cells and confirm the in vivo activity of WRN inhibition using an MSI-H mouse xenograft model. This work elucidates a regulatory mechanism for WRN that may facilitate identification of new therapeutic modalities, and highlights the use of SMT as a tool for drug discovery and mechanism-of-action studies.

100 Deals associated with WRN Inhibitor(Eikon)

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