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Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma.

ABSTRACT: CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogenic pathways in in vitro studies. Detailed understanding of the mechanism of action of CARM1 in oncogenesis has been limited by a lack of selective tool compounds, particularly for in vivo studies. We describe the identification and characterization of, to our knowledge, the first potent and selective inhibitor of CARM1 that exhibits anti-proliferative effects both in vitro and in vivo and, to our knowledge, the first demonstration of a role for CARM1 in multiple myeloma (MM). EZM2302 (GSK3359088) is an inhibitor of CARM1 enzymatic activity in biochemical assays (IC50?=?6?nM) with broad selectivity against other histone methyltransferases. Treatment of MM cell lines with EZM2302 leads to inhibition of PABP1 and SMB methylation and cell stasis with IC50 values in the nanomolar range. Oral dosing of EZM2302 demonstrates dose-dependent in vivo CARM1 inhibition and anti-tumor activity in an MM xenograft model. EZM2302 is a validated chemical probe suitable for further understanding the biological role CARM1 plays in cancer and other diseases.

SUBMITTER: Drew AE

PROVIDER: S-EPMC5740082 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma.

Drew Allison E AE Moradei Oscar O Jacques Suzanne L SL Rioux Nathalie N Boriack-Sjodin Ann P AP Allain Christina C Scott Margaret Porter MP Jin Lei L Raimondi Alejandra A Handler Jessica L JL Ott Heidi M HM Kruger Ryan G RG McCabe Michael T MT Sneeringer Christopher C Riera Thomas T Shapiro Gideon G Waters Nigel J NJ Mitchell Lorna H LH Duncan Kenneth W KW Moyer Mikel P MP Copeland Robert A RA Smith Jesse J Chesworth Richard R Ribich Scott A SA

Scientific reports 20171221 1

CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogenic pathways in in vitro studies. Detailed understanding of the mechanism of action of CARM1 in oncogenesis has been limited by a lack of selective tool compounds, particularly for in vivo studies. We ...[more]

PMID: 29269946

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Project description:Apoptosis induction by death receptor (DR)-specific agonistic antibodies is a potentially effective antitumor therapy. Nonetheless, to date, all conventional DR-targeting antibodies that induce apoptosis via FcγR-dependent DR clustering failed to show clinical efficacy. HexaBody-DR5/DR5 (GEN1029) has been developed to overcome full FcγR dependence. HexaBody-DR5/DR5 is a mixture of 2 noncompeting DR5-specific immunoglobulin G1 (IgG1) antibodies, each with an E430G mutation in the Fc domain. This mutation enhances Fc-Fc interactions, resulting in antibody hexamerization, followed by FcγR-independent clustering of DR5 molecules. This unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent preclinical antitumor activity in various solid cancers. In this study, we explored the preclinical activity of HexaBody-DR5/DR5 in multiple myeloma (MM), because MM cells are known to express DR5. In bone marrow samples from 48 MM patients, HexaBody-DR5/DR5 induced potent cytotoxicity of primary MM cells. Importantly, HexaBody-DR5/DR5 mediated the highest cytotoxic activity in samples from relapsed/refractory MM patients, including those who are refractory to daratumumab. This improved cytotoxic activity was observed only in patients who received their last anti-MM treatment <1 month ago, suggesting that anti-MM drugs sensitized MM cells to HexaBody-DR5/DR5. Supporting this, bortezomib combined with HexaBody-DR5/DR5 synergistically increased cytotoxicity in MM cells in 7 of 11 newly diagnosed patients. Lenalidomide also synergized with HexaBody-DR5/DR5, but only via its immunomodulatory effects, presumably by enhancing the antibody-dependent cellular cytotoxicity activity of HexaBody-DR5/DR5. Daratumumab showed additive effects when combined with HexaBody-DR5/DR5. In conclusion, the results of this preclinical study indicate a therapeutic potential for HexaBody-DR5/DR5, especially in recently treated relapsed/refractory MM patients.

Dataset Information

Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma.

Publications

Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma.

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