Structure-Based Design of the Indole-Substituted Triazolopyrimidines as New EED–H3K27me3 Inhibitors for the Treatment of Lymphoma

Abstract

Interrupting the embryonic ectoderm development (EED)–H3K27me3 interaction represents a promising strategy to allosterically inhibit polycomb repressive complex 2 (PRC2) for cancer therapy. In this work, we report the structure-based design of new triazolopyrimidine-based EED inhibitors, which structurally feature the electron-rich indole ring at the C8 position. Particularly, ZJH-16 directly binds to EED (HTRF IC50 = 2.72 nM, BLI K D = 4.4 nM) and potently inhibits the growth of KARPAS422 and Pfeiffer cells. In both cells, ZJH-16 is selectively engaged with EED and reduces H3K27 trimethylation levels. ZJH-16 inhibits the gene silencing function of PRC2 in KARPAS422 cells. ZJH-16 possesses favorable pharmacokinetic (PK) profiles with an excellent oral bioavailability (F = 94.7%). More importantly, ZJH-16 shows robust tumor regression in the KARPAS422 xenograft model after oral administration with the tumor growth inhibition reaching nearly 100%. The robust antitumor efficacy and favorable PK profiles of ZJH-16 warrant further advanced preclinical development for lymphoma treatment.

Targeting polycomb repressor complex 2‐mediated bivalent promoter epigenetic silencing of secreted frizzled‐related protein 1 inhibits cholangiocarcinoma progression

“…In contrast, post‐transcriptional modification of SUZ12 promotes catalysis and facilitates suppression of target genes by enhancing PRC2 function. 51 Targeting EZH2, a variety of inhibitors have now emerged, including those targeting EZH2‐specific H3K27me3 catalytic activity 52 , 53 and those that decrease the protein levels of EZH2 or EED. 33 , 54 DNA methyltransferase inhibitors including decitabine have significant inhibitory effects on DNMT3a, DNMT3b and DNMT1 and are approved for the treatment of hematologic tumours and expanding into solid tumours.…”

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

“…In addition, hybrid 63 (1.0 mg/kg, oral administration) also possessed favorable pharmacokinetic profiles in rats with CL of 29 L/h/kg, V ss of 3.0 L/kg, and bioavailability of 67%. [80] In the KARPAS422 xenografted mice model, ZJH-16 (25 mg/kg, oral administration) showed complete regression without abnormal behavior or body weight loss. Moreover, no damage to major organs or abnormal behavior or mice death was observed even at 500 mg/kg, demonstrating its excellent safety profiles.…”

“…[1,2,4]Triazolo[4,3‐ c ]pyrimidine‐indole hybrid 64 (ZJH‐16, IC 50 : 220 and 130 nM) exhibited profound activity against KARPAS422 and Pfeiffer cancer cell lines and could remarkably inhibit various tumor‐related signaling pathways, including the Wnt signaling pathway, Rap1 signaling pathway, PI3K‐Akt signaling pathway, extracellular matrix, receptor binding pathway, and focal adhesion kinase signaling pathway. [ 80 ] In the KARPAS422 xenografted mice model, ZJH‐16 (25 mg/kg, oral administration) showed complete regression without abnormal behavior or body weight loss. Moreover, no damage to major organs or abnormal behavior or mice death was observed even at 500 mg/kg, demonstrating its excellent safety profiles.…”

The roles of EZH2 in cancer and its inhibitors

“…Based on the structure–activity relationship of EED 226, researchers discovered a new EED inhibitor ZJH-16 by changing the substituent type. ZJH-16 directly binds to the H3K27me3 binding pocket of EED with high affinity (HTRF IC 50 = 2.72 nM, BLI Kd = 4.4 nM), and ZJH-16 demonstrates volatile pharmaceutical (PK) properties and robust antagonist efficiency in a KARPAS-422 xenograft model [ 99 ]. The EED inhibitor BR001, which demonstrated significant EED targeting activity in competitive binding tests and had an IC 50 value of 4.5 nM, was found based on the structure of EED226 and utilizing the scaffold picking approach.…”