1258P HJM-353: A potent, selective and orally bioavailable EED inhibitor with robust anti-tumor activities

Abstract

Polycomb Repressive Complex 2 (PRC2), a multimeric complex that catalyzes the methylation of histone H3 at lysine 27 with core subunits EZH2, EED and SUZ12, functions as an epigenetic modulator in regulating cell proliferation and development. Dysregulation of the PRC2 complex is implicated in hematological and solid malignancies and shown to correlate with poor prognosis in cancers. Recently EZH2 inhibitor Tazemetostat has been approved by FDA for the treatment of advanced epithelioid sarcoma and follicular lymphoma. However, acquired resistant mutations in EZH2 and complementary activation of EZH1 might impair the effectiveness of this class of PRC2 inhibitors. Targeting the allosteric subunit EED represents a new strategy to fully inhibit PRC2 activity and address the limitations of EZH2 inhibition. Herein, we report HJM-353 as an efficacious EED inhibitor for cancer therapy. In vitro activities of HJM-353 were assessed by CTG assay and Western blot in EZH2 mutant human cell lines.In vivo anti-tumor activities of HJM-353 were evaluated in DLBCL and gastric cancer xenograft models.Pharmacokinetic/pharmacodynamics correlation of HJM-353 was determined by LC-MS/MS, Western blot and Q-PCR. HJM-353 effectively reduced H3K27me3 level and inhibited cell proliferation with an IC50 of 33.8 nM in WSU-DLCL2 cells. It displayed favorable PK properties and induced complete tumor regression in KARPAS-422 derived DLBCL xenograft model. Plasma concentration of HJM-353 correlated with the inhibition of H3K27me3 and upregulation of PRC2 target genes in tumors, indicating a clear PK/PD relationship in the xenografts. In addition, HJM-353 caused tumor stasis as MAK683 did in a xKATO-III gastric xenograft model. In summary, HJM-353 is a potent, selective and orally bioavailable EED inhibitor with robust anti-tumor activities. We are developing HJM-353 for the treatment of hematological malignancies and solid tumors and expect to file an IND in the second half of 2022.