Delving into the Latest Updates on UNC0631 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

H3K9me3

Mechanism

H3K9me3 inhibitors(Histone 3 lysine 9 trimethylation protein inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

University of North Carolina System

Active Organization

University of North Carolina System

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Background and AimsCholangiocarcinoma (CCA) is a highly malignant epithelial tumor of the biliary tree with poor prognosis. In the current study, we present evidence that the histone‐lysine methyltransferase G9a is up‐regulated in human CCA and that G9a enhances CCA cell growth and invasiveness through regulation of the Hippo pathway kinase large tumor suppressor 2 (LATS2) and yes‐associated protein (YAP) signaling pathway.Approach and ResultsKaplan‐Meier survival analysis revealed that high G9a expression is associated with poor prognosis of CCA patients. In experimental systems, depletion of G9a by small interfering RNA/short hairpin RNA or inhibition of G9a by specific pharmacological inhibitors (UNC0642 and UNC0631) significantly inhibited human CCA cell growth in vitro and in severe combined immunodeficient mice. Increased G9a expression was also observed in mouse CCA induced by hydrodynamic tail vein injection of notch intracellular domain (NICD) and myr‐Akt. Administration of the G9a inhibitor UNC0642 to NICD/Akt‐injected mice reduced the growth of CCA, in vivo. These findings suggest that G9a inhibition may represent an effective therapeutic strategy for the treatment of CCA. Mechanistically, our data show that G9a‐derived dimethylated H3K9 (H3K9me2) silenced the expression of the Hippo pathway kinase LATS2, and this effect led to subsequent activation of oncogenic YAP. Consequently, G9a depletion or inhibition reduced the level of H3K9me2 and restored the expression of LATS2 leading to YAP inhibition.ConclusionsOur findings provide evidence for an important role of G9a in cholangiocarcinogenesis through regulation of LATS2‐YAP signaling and suggest that this pathway may represent a potential therapeutic target for CCA treatment.

100 Deals associated with UNC0631

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