Claims for Patent: 9,949,999

Summary for Patent: 9,949,999

Title:	Inhibitors of human EZH2, and methods of use thereof
Abstract:	The invention relates to inhibition of wild-type and certain mutant forms of human histone methyltransferase EZH2, the catalytic subunit of the PRC2 complex which catalyzes the mono- through tri-methylation of lysine 27 on histone H3 (H3-K27). In one embodiment the inhibition is selective for the mutant form of the EZH2, such that trimethylation of H3-K27, which is associated with certain cancers, is inhibited. The methods can be used to treat cancers including follicular lymphoma and diffuse large B-cell lymphoma (DLBCL). Also provided are methods for identifying small molecule selective inhibitors of the mutant forms of EZH2 and also methods for determining responsiveness to an EZH2 inhibitor in a subject.
Inventor(s):	Copeland; Robert A. (Lexington, MA), Richon; Victoria M. (Wellesley, MA), Scott; Margaret D. (Beverly, MA), Sneeringer; Christopher J. (San Francisco, CA), Kuntz; Kevin W. (Woburn, MA), Knutson; Sarah K. (Cambridge, MA), Pollock; Roy M. (Medford, MA)
Assignee:	Epizyme, Inc. (Cambridge, MA)
Application Number:	15/132,724
Patent Claims:	1. A method of inhibiting Enhancer of Zeste Homolog 2 (EZH2), the method comprising contacting a cell expressing a Y641 mutant of the EZH2 polypeptide of SEQ ID NO: 1, a Y646 mutant of the EZH2 polypeptide of SEQ ID NO: 3, or a Y602 mutant of the EZH2 polypeptide of SEQ ID NO: 5 with an inhibitor of EZH2 in an amount effective to inhibit the conversion of H3-K27 to trimethylated H3-K27 in the cell. 2. The method of claim 1, wherein the inhibition is selective inhibition. 3. The method of claim 1, wherein the Y641 mutant of the EZH2 polypeptide is a Y641F mutation. 4. The method of claim 1, wherein the Y641 mutant of the EZH2 polypeptide is a Y641H mutation. 5. The method of claim 1, wherein the Y641 mutant of the EZH2 polypeptide is a Y641N mutation. 6. The method of claim 1, wherein the Y641 mutant of the EZH2 polypeptide is a Y641S mutation. 7. The method of claim 1, wherein the cell expressing the Y641 mutant of the EZH2 polypeptide is a cancer cell. 8. The method of claim 7, wherein the cancer cell is a lymphoma cell. 9. The method of claim 8, wherein the lymphoma is a B-cell lymphoma. 10. The method of claim 8, wherein the lymphoma is follicular lymphoma. 11. The method of claim 8, wherein the lymphoma is diffuse large B-cell lymphoma (DLBCL). 12. The method of claim 7, wherein the cancer cell is a melanoma cell. 13. The method of claim 1, wherein the cell expressing the Y641 mutant of the EZH2 polypeptide is a cell obtained from a subject. 14. The method of claim 1, wherein the method further comprises obtaining the cell expressing the Y641 mutant of the EZH2 polypeptide from a subject. 15. The method of claim 1, wherein the cell expressing the Y641 mutant of the EZH2 polypeptide is a cell of a subject having cancer. 16. The method of claim 15, wherein the subject is a human subject. 17. The method of claim 15, wherein the contacting comprises administering the EZH2 inhibitor to the subject.