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 in leukemia; EHZ2 in breast, gastric, and prostate cancers; and NSD1 and CARM1 in acute myeloid leukemia (AML).
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. This invention describes a series of small molecule inhibitors of PMTs, including CARM1, identified by MSK investigators through a high throughput screening approach.
- These compounds display high selectivity for PMTs
- Compounds show remarkable inhibitory activity in vitro to CARM1
- Potential therapeutic application in AML (activity demonstrated in AML cell lines)
AML is the most common type of adult acute leukemia, accounting for 38% of new leukemia patients in 2015. In 2015, there were an estimated 20,830 patients diagnosed with AML in the U.S., translating into a potential market size of ~$2B assuming a $100K annual cost per patient.
U.S. National Patent applications 14/353,815 and 14/784,078 filed on April 24, 2014 and October 13, 2015, respectively; and Provisional application 62/244,825 filed on October 22, 2015
Minkui Luo, PhD, Laboratory Head, Memorial Hospital Research Laboratories, Memorial Sloan Kettering