Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor

Honma, Daisuke; Kanno, Osamu; Watanabe, Jun; Kinoshita, Junzo; Hirasawa, Makoto; Nosaka, Emi; Shiroishi, Machiko; Takizawa, Takeshi; Yasumatsu, Isao; Horiuchi, Takao; Nakao, Akira; Suzuki, Keisuke; Yamasaki, Tomonori; Nakajima, Katsuyoshi; Hayakawa, Miho; Yamazaki, Takanori; Yadav, Ajay Singh; Adachi, Nobuaki

doi:10.1111/cas.13326

Cited by 98 publications

(86 citation statements)

References 64 publications

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“…OR‐S1 had a significant antitumor effect in comparison with other established EZH2 or EZH1/2 inhibitors, including the EZH2‐specific inhibitor GSK126, and markedly impaired the growth of all MM cells in vitro and in vivo, including a unique PDX model, with single‐agent administration. When compared to other EZH1/2‐targeting compounds, OR‐S1 suppresses the enzymatic activity of EZH1 more potently than and other EZH2 inhibitors . This difference would be one of the reasons why OR‐S1 showed better growth inhibition efficacy than other inhibitors.…”

Section: Discussionmentioning

confidence: 98%

“…Therefore, we hypothesized that EZH1, in addition to EZH2, is also important for stem cell maintenance in MM and that dual inhibition of EZH1/2 could eradicate myeloma stem cells as seen in acute myeloid leukemia. Here, we used a novel orally bioavailable EZH1/2 dual inhibitor, OR‐S1, which potently inhibits both EZH1 and EZH2 . This translational tool enabled us to investigate the role of EZH1/2 in myeloma stem cells by analyzing SP cells.…”

Section: Introductionmentioning

confidence: 99%

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Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

Nakagawa

Fujita²,

Katsumoto³

et al. 2018

Cancer Science

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Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug‐resistant myeloma stem cells. Side population (SP) cells show cancer stem cell‐like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non‐SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR‐S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient‐derived xenograft model. Moreover, long‐term continuous dosing of OR‐S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR‐S1, leading to significant advances in the treatment of MM.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

Nakagawa

Fujita²,

Katsumoto³

et al. 2018

Cancer Science

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“…described ( R )‐OR‐S1 and ( R )‐OR‐S2 as dual inhibitors of EZH1/2 suppressing trimethylation of histone H3K27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B‐cell lymphoma as well as solid cancers, without exhibiting severe toxicity in rats . When tested in acute myeloid leukemia mouse models and patient‐derived xenograft models, ( R )‐OR‐S1 reduced the number of leukemia stem cells, impaired leukemia progression, prolonged survival, and in combination with cytarabine prevented relapse, thus indicating the possibility of EZH1/2 dual inhibitors for clinical applications mainly in combination therapy.…”

Section: A Fundamental Step For Highly Potent and Selective Catalyticmentioning

confidence: 98%

Six Years (2012–2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2‐Pyridone Compounds

Fioravanti

Stazi

Zwergel

et al. 2018

The Chemical Record

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Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2 (PRC2), catalyzes the methylation of lysine 27 of histone H3 (H3K27) up to its trimethylated form (H3K27me), inducing by this way block of transcription and gene silencing. High levels of H3K27me3 have been found in both hematological malignancies and solid cancers, due to EZH2 overexpression and/or EZH2 mutation. From 2012, a number of highly potent and selective catalytic inhibitors of EZH2 have been reported, almost all bearing a 2‐pyridone group in their structure. Typically, 2‐pyridone inhibitors are selective for EZH2 over other methyltransferases, and some of them are specific for EZH2 over EZH1, others behave as dual EZH2/EZH1 inhibitors. The 2‐pyridone moiety was crucial for the enzyme inhibition, as revealed later by crystallographic studies because it occupies partially the site for the co‐substrate SAM (or the by‐product, SAH) in the binding pocket of the enzyme, accounting for the SAM‐competitive mechanism of action displayed by all the 2‐pyridone inhibitors. The 2‐pyridone warhead is linked to a support substructure, that can be either a bicyclic heteroaromatic ring (such as indazole, see for instance EPZ005687 and UNC1999, or indole, see for instance GSK126, EI1, and the more recent CPI‐1205) or a simple monocyclic (hetero) aromatic ring (tazemetostat, MC3629, (R)‐OR‐S1/2), eventually annulated with the amide chain carrying the 2‐pyridone group (3,4‐dihydroisoquinoline‐1(2H)‐ones). Different substitutions at the support moiety influence the pharmacokinetics and pharmacodynamics of the compounds as well as their water solubility. In cancer diseases, the first reported 2‐pyridone inhibitors displayed high antiproliferative effects in vitro and in vivo in lymphomas characterized by mutant EZH2 (such as Y641N), but the most recent compounds exert their anticancer activity against tumors with wild‐type EZH2 as well. The dual EZH2/1 inhibitors have been recently reported to be more effective than EZH2 selective inhibitors in specific leukemias including leukemias cancer stem cells.

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“…Thus, dual inhibition of EZH1/2 with an EZH1/2 dual inhibitor is effective for disrupting PRC2. Indeed, OR‐S1 suppresses H3K27me3 more potently in cells than UNC1999 and other EZH2 inhibitors . This drug is more effective than other selective EZH2 inhibitors in hematological cell lines including AML and acute lymphoblastic leukemia (ALL) cell lines harboring fusion genes, DLBCL cell lines with EZH2 gain‐of‐function mutations, and peripheral T‐cell lymphoma and MM cell lines .…”

Section: Role Of Ezh1 In Hematological Malignancies and Targeting Thementioning

confidence: 99%

“…71 OR-S1 reduces the number of LSC, suppresses leukemia progression, and prolongs survival without serious sideeffects. 70,71 This drug, which induces differentiation and eradicates quiescent LSC, shows a synergistic effect on LSC with conventional chemotherapy agents, similar to the effect of all-trans-retinoic acid in acute promyelocytic leukemia. Thus, dual inhibition of EZH1/2 with an EZH1/2 dual inhibitor is effective for disrupting PRC2.…”

Section: Malignancie S and Targeting Therapy Against Ezh1/2mentioning

confidence: 99%

Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies

Nakagawa

Kitabayashi²

2018

Cancer Science

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Polycomb group (PcG) proteins regulate the expression of target genes by modulating histone modifications and are representative epigenetic regulators that maintain the stemness of embryonic and hematopoietic stem cells. Histone methyltransferases enhancer of zeste homolog 1 and 2 (EZH1/2), which are subunits of polycomb repressive complexes (PRC), are recurrently mutated or highly expressed in many hematological malignancies. EZH2 has a dual function in tumorigenesis as an oncogene and tumor suppressor gene, and targeting PRC2, in particular EZH1/2, for anticancer therapy has been extensively developed in the clinical setting. Here, we review the oncogenic function of EZH1/2 and introduce new therapeutic drugs targeting these enzymes.

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Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor

Cited by 98 publications

References 64 publications

Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

Six Years (2012–2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2‐Pyridone Compounds

Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies

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