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Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple
Allison E Drew1, Oscar Moradei2, Suzanne L Jacques2
1Epizyme, Inc., Cambridge, Massachusetts, USA. adrew@epizyme.com.
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.
Insights
Researchers developed EZM2302, the first potent and selective CARM1 inhibitor, showing anti-cancer effects in multiple myeloma (MM) models. This chemical probe offers new insights into CARM1
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- CARM1 (co-activator-associated arginine methyltransferase 1) is an enzyme involved in gene regulation and RNA processing.
- Overexpression of CARM1 is linked to various cancers, but its precise role in oncogenesis is unclear due to a lack of specific inhibitors.
- Understanding CARM1's function is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To identify and characterize the first potent and selective inhibitor of CARM1.
- To evaluate the anti-proliferative effects of the inhibitor in vitro and in vivo.
- To demonstrate the role of CARM1 in multiple myeloma (MM) and its potential as a therapeutic target.
Main Methods:
- Biochemical assays to determine CARM1 inhibitory activity and selectivity.
- In vitro studies using multiple myeloma cell lines to assess drug efficacy.
- In vivo studies using a multiple myeloma xenograft mouse model to evaluate anti-tumor activity and pharmacodynamics.
Main Results:
- EZM2302 was identified as a potent CARM1 inhibitor with an IC50 of 6 nM and high selectivity against other methyltransferases.
- EZM2302 demonstrated nanomolar potency in inhibiting PABP1 and SMB methylation and causing cell stasis in MM cell lines.
- Oral administration of EZM2302 showed dose-dependent CARM1 inhibition and significant anti-tumor activity in an MM xenograft model.
Conclusions:
- EZM2302 is the first validated chemical probe for CARM1, suitable for further research.
- The study establishes a role for CARM1 in multiple myeloma.
- EZM2302 exhibits promising anti-cancer potential for MM and other CARM1-associated diseases.
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