2. Academic Validation
  3. EEDi-5285: An Exceptionally Potent, Efficacious, and Orally Active Small-Molecule Inhibitor of Embryonic Ectoderm Development

EEDi-5285: An Exceptionally Potent, Efficacious, and Orally Active Small-Molecule Inhibitor of Embryonic Ectoderm Development

  • J Med Chem. 2020 Jul 9;63(13):7252-7267. doi: 10.1021/acs.jmedchem.0c00479.
Rohan Kalyan Rej 1 2,  Changwei Wang 1 2,  Jianfeng Lu 1 2,  Mi Wang 1 2,  Elyse Petrunak 3,  Kaitlin P Zawacki 1 2,  Donna McEachern 1 2,  Ester Fernandez-Salas 1 2,  Chao-Yie Yang 1 2,  Lu Wang 1 4,  Ruiting Li 1 4,  Krishnapriya Chinnaswamy 3,  Bo Wen 1 4,  Duxin Sun 1 4,  Jeanne Stuckey 1 3,  Yunlong Zhou 5,  Jianyong Chen 5,  Guozhi Tang 5,  Shaomeng Wang 6
Affiliations

Affiliations

  • 1 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Ascentage Pharma Group, Suzhou, Jiangsu 215216, China.
  • 6 Rogel Cancer Center, Departments of Internal Medicine and Pharmacology, Medical School, and Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 32580550 DOI: 10.1021/acs.jmedchem.0c00479
Abstract

Inhibition of embryonic ectoderm development (EED) is a new Cancer therapeutic strategy. Herein, we report our discovery of EEDi-5285 as an exceptionally potent, efficacious, and orally active EED inhibitor. EEDi-5285 binds to the EED protein with an IC50 value of 0.2 nM and inhibits cell growth with IC50 values of 20 pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively, carrying an EZH2 mutation. EEDi-5285 is approximately 100 times more potent than EED226 in binding to EED and >300 times more potent than EED226 in inhibition of cell growth in the KARPAS422 cell line. EEDi-5285 has excellent pharmacokinetics and achieves complete and durable tumor regression in the KARPAS422 xenograft model in mice with oral administration. The cocrystal structure of EEDi-5285 in a complex with EED defines the precise structural basis for their high binding affinity. EEDi-5285 is the most potent and efficacious EED inhibitor reported to date.

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