Inhibitors of human EZH2, and methods of use thereof
First Claim
1. A method of treating cancer in a subject in need thereof comprisingdetecting the presence of a mutation in the EZH2 substrate pocket domain of SEQ ID NO:
- 7, in a sample from the subject, wherein said detecting comprises screening, at amino acid positions Y641, A677, and A687 of EZH2 of SEQ ID NO;
1, for the presence of at least one mutation, wherein the mutation at amino acid position Y641 is selected from the group consisting of a substitution of phenylalanine (F) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641F);
a substitution of histidine (H) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641H);
a substitution of asparagine (N) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641N);
a substitution of serine (S) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641S); and
a substitution of cysteine (C) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641C), wherein the mutation at amino acid position A677 is a substitution of glycine (G) for the wild type residue alanine (A) at amino acid position 677 of SEQ ID NO;
1 (A677G), wherein the mutation at amino acid position A687 is a substitution of valine (V) for the wild type residue alanine (A) at amino acid position 687 of SEQ ID NO;
1 (A687V), and wherein the mutation increases EZH2 trimethylation of Lys27 of histone H3 (H3-K27); and
identifying the subject as a candidate for treatment with an EZH2 inhibitor based on the presence of a detected EZH2 mutation;
administering a therapeutically effective amount of an EZH2 inhibitor to the identified subject, wherein the EZH2 inhibitor inhibits the conversion of H3-K27 to trimethylated H3-K27.
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Accused Products
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.
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Citations
13 Claims
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1. A method of treating cancer in a subject in need thereof comprising
detecting the presence of a mutation in the EZH2 substrate pocket domain of SEQ ID NO: - 7, in a sample from the subject, wherein said detecting comprises screening, at amino acid positions Y641, A677, and A687 of EZH2 of SEQ ID NO;
1, for the presence of at least one mutation, wherein the mutation at amino acid position Y641 is selected from the group consisting of a substitution of phenylalanine (F) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641F);
a substitution of histidine (H) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641H);
a substitution of asparagine (N) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641N);
a substitution of serine (S) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641S); and
a substitution of cysteine (C) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO;
1 (Y641C), wherein the mutation at amino acid position A677 is a substitution of glycine (G) for the wild type residue alanine (A) at amino acid position 677 of SEQ ID NO;
1 (A677G), wherein the mutation at amino acid position A687 is a substitution of valine (V) for the wild type residue alanine (A) at amino acid position 687 of SEQ ID NO;
1 (A687V), and wherein the mutation increases EZH2 trimethylation of Lys27 of histone H3 (H3-K27); andidentifying the subject as a candidate for treatment with an EZH2 inhibitor based on the presence of a detected EZH2 mutation; administering a therapeutically effective amount of an EZH2 inhibitor to the identified subject, wherein the EZH2 inhibitor inhibits the conversion of H3-K27 to trimethylated H3-K27. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
- 7, in a sample from the subject, wherein said detecting comprises screening, at amino acid positions Y641, A677, and A687 of EZH2 of SEQ ID NO;
Specification