Epigenetic Methylation inhibitors displaying anti-tumor activity


Diffuse intrinsic pontine glioma (DIPG) is a lethal malignant tumor that arises from the middle portion of the brain stem and usually affects children with a poor prognosis, as there are no surgical options for providing relief to patients. Conventional chemotherapy as well as radiation therapy provide minimal life extension and palliative relief at best. More than 85% of DIPG cases are identified with an H3K27M mutation, which implies its essential role in tumorigenesis and growth, further raising its appeal as a therapeutic target. H3K27M mutation causes a global reduction of K27 methylation and an open chromatin that is believed to modify cellular gene expression to promote tumor development. Inhibiting related demethylase activity is one of two major pharmacologic paths for restoring global H3K27 methylation.

Technology Overview

Researchers have developed a series of DNA methylation inhibitors, related to the known benchmark inhibitor GSK-J4/J1 that have more favorable physical properties for use in vivo, including stability in the bloodstream, transport of the blood brain barrier, and therefore greater biodistribution in the brain. These inhibitors have demonstrated promising anti-tumor activity in pre-clinical intracranial xenograft models. This approach has thus led to the discovery of new DNA methylation inhibitors from modified 4-amino pyrimidine compounds for treatment of DIPG and potentially other brain cancers with significantly enhanced in vivo efficacy of the drug treatment.


GSK-J1/J4 restores K27 methylation and compacts chromatin while demonstrating potent anti-tumor activity in preclinical models. The future application of these modified 4-amino pyrimidine analogs of GSK-J4/J1 may also be applied to DIPG or other brain cancers with H3K27M mutations as single therapies or in combinations with other chemotherapeutics or radiation.


Diffuse intrinsic pontine glioma (DIPG) and other brain cancers with H3K27M mutation

URV Reference Number: 1-22043
Patent Information:
For Information, Contact:
McKenna Geiger
Licensing Manager
University of Rochester
Frank (Hal) Ebetino
Venkatesan Srinivasan
Rintaro Hashizume
Robert Boeckman, Jr.