Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies

Abstract

Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the lowmolecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.

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

“…Importantly, ZJH-16 exhibited excellent oral bioavailability ( F = 94.7%). In contrast, after oral dosing of EED226 at 2 mg/kg, the AUC, T 1/2 , and F were 1948 nM h, 1.6 h, and 62%, respectively . The results demonstrate that ZJH-16 has a better oral bioavailability than EED226.…”

“…In contrast, after oral dosing of EED226 at 2 mg/kg, the AUC, T 1/2 , and F were 1948 nM h, 1.6 h, and 62%, respectively. 36 The results demonstrate that ZJH-16 has a better oral bioavailability than EED226. Collectively, the PK studies suggest that ZJH-16 has acceptable PK profiles in male rats and is suitable for carrying out further in vivo antitumor studies.…”

“…Further structural modifications on EED226 have led to the discovery of the clinical candidate MAK683, which is currently in phase I/II clinical trials to evaluate the safety and efficacy of MAK683 in adult patients with advanced malignancies (ClinicalTrials.gov identifier: NCT02900651). Based on the binding mode of EED226 with EED and previously reported structure–activity relationship (SAR) studies, we performed the structure-based design and further structural modifications, leading to the discovery of a series of the indole-substituted pyrimidazole or pyrimidothiazole derivatives as new EED inhibitors, of which ZJH-16 directly binds to the H3K27me3 binding pocket of EED with an exceptionally high affinity (HTRF IC 50 = 2.72 nM, BLI IC 50 = 4.4 nM) and is about 5-fold more potent than EED226. ZJH-16 significantly reduces H3K27me3 levels and inhibits proliferation of both KARPAS422 and Pfeiffer cells.…”

Fused Pyridine Derivatives: Synthesis and Biological Activities

“…Lastly, compounds containing triazolopyridine ring were evaluated for their bioactivities, such as anti-inflammatory, p38R, 11beta-hydroxysteroid dehydrogenase-type 1 (11beta-HSD-1), prolylhydroxylase domain-1 (PHD-1), myeloperoxidase, tubulin polymerization, polycomb repressive complex 2 (PRC2) inhibitory, HIV-1 allosteric inhibitor activity, mGlu receptor 2 (mGluR2) PAM, muscarinic acetylcholine receptor subtype 1 (M1) PAM, and retinoic acid receptor-related orphan nuclear receptor gama-t (RORγt) inverse agonist [174,[291][292][293][294][295][296][297][298][299][300][301][302][303].…”

Critical Roles of Polycomb Repressive Complexes in Transcription and Cancer

“…Furthermore, gene expression microarray and Chip-PCR experiments revealed that PRC2-regulated gene expression was significantly increased by treatment with EED226 and was similar to that of EZH2 catalytic inhibitor (EI1) treatment, demonstrating that EED226 also has a significant inhibitory effect on the gene-silencing function of PRC2 [ 278 ]. Interestingly, although EED226 failed to enter clinical trials, another EED inhibitor, MAK683, developed on the basis of this scaffold, is currently in phase 2 clinical trials for the treatment of lymphoma ( Table 3 ) [ 280 ]. Moreover, EEDi-5285 is the most potent EED inhibitor that has been reported, and it achieves complete and long-lasting tumor regression in mice, further suggesting great potential for the treatment of PRC2-dependent cancers by inhibiting the EED-H3K27me3 interaction [ 279 ].…”