2. Academic Validation
  3. A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors

A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors

  • ACS Med Chem Lett. 2022 Feb 10;13(3):377-387. doi: 10.1021/acsmedchemlett.1c00448.
Rui Liang 1,  Daisuke Tomita 1,  Yusuke Sasaki 1,  John Ginn 1,  Mayako Michino 1,  David J Huggins 1 2,  Leigh Baxt 1,  Stacia Kargman 1,  Maaz Shahid 3 4 5,  Kazuyoshi Aso 1,  Mark Duggan 6,  Andrew W Stamford 1,  Elisa DeStanchina 7,  Nigel Liverton 1,  Peter T Meinke 1 8,  Michael A Foley 1,  Richard E Phillips 3 4 5
Affiliations

Affiliations

  • 1 Tri-Institutional Therapeutics Discovery Institute, 413 East 69th Street, New York, New York 10021, United States.
  • 2 Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York 10021, United States.
  • 3 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 4 Epigenetics Program, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, United States.
  • 5 Abramson Cancer Center, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, United States.
  • 6 LifeSci Consulting, LLC., 18243 SE Ridgeview Drive, Tequesta, Florida 33469, United States.
  • 7 Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
  • 8 Department of Pharmacology, Weill Cornell Medical College, New York, New York 10021, United States.
PMID: 35300079 DOI: 10.1021/acsmedchemlett.1c00448
Abstract

Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in Cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S. Food and Drug Administration approval following promising clinical responses in Cancer patients. However, the current array of EZH2 inhibitors have poor brain penetrance, limiting their use in patients with central nervous system malignancies, a number of which have been shown to be sensitive to EZH2 inhibition. To address this need, we have identified a chemical strategy, based on computational modeling of pyridone-containing EZH2 Inhibitor scaffolds, to minimize P-glycoprotein activity, and here we report the first brain-penetrant EZH2 Inhibitor, TDI-6118 (compound 5). Additionally, in the course of our attempts to optimize this compound, we discovered TDI-11904 (compound 21), a novel, highly potent, and peripherally active EZH2 Inhibitor based on a 7 member ring structure.

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