Epigenetic control of gene expression includes post-translational histone modifications, allowing chromatin to switch between a condensed state (heterochromatin) in which gene transcription is repressed, and a loose state (euchromatin) in which gene transcription is activated. Protein methyltransferases (PMTs) are one of the classes of enzymes functioning to modify histones by methylating lysine or arginine residues, thereby controlling gene expression. Several PMTs have been implicated in human cancers, including DOT1L, EZH2, PRMT5, PRMT1, and CARM1. CARM1 has been implicated in multiple cancer types, including breast cancer and hematological malignancies.
While small molecule inhibitors have been successfully developed for chromatin-modifying enzymes such as histone deacetylases (i.e., Farydak for multiple myeloma and Istodax for PTCL/CTCL), PMT inhibitors are currently in early stages of clinical development. MSK scientists, through extensive synthetic efforts guided by X-ray crystallography and computational modeling, have developed a rationally-designed CARM 1 inhibitor that, upon cellular internalization, rapidly converts into its active forms. Uniquely, this inhibitor has been shown to demonstrate anti-metastatic activity in breast cancer cell lines.
- Highly potent and selective inhibitor of CARM1
- Prodrug property expected to show superior pharmacological kinetics compared with other CARM1 inhibitors
- Anti-metastatic effects against breast cancer cells is a novel mechanism-of-action distinct from other CARM1 inhibitors
In 2018, there were an estimated 330K patients diagnosed with breast cancer in the U.S., 80% of those exhibiting invasive breast cancer. Given that breast cancer mortality rates are largely attributed to metastasis, targeting metastatic pathways via CARM1 inhibition could lead to long-term cures.
STAGE OF DEVELOPMENT
National application filed in the U.S.
Minkui Luo, PhD, Laboratory Head, Memorial Hospital Research Laboratories, Memorial Sloan Kettering
E-mail: [email protected]