Substituted 3-amino-5-phenylbenzamide compounds as covalent inhibitors of enhancer zeste homolog 2 (EZH2) and proteolysis-targeting chimeric derivatives thereof (PROTACs) that induce degradation of EZH2
Disclosed are covalent inhibitors of enhancer zeste homolog 2 (EZH2) which may be utilized as EZH2 targeting agents. The disclosed compounds may be characterized as substituted 3-amino-5-phenylbenzamide compounds. The disclosed compounds may be utilized as covalent inhibitors of EZH2 and further may be derivatized to form proteolysis-targeting chimeric molecules (PROTACs) that target EZH2 for degradation. The disclosed compounds and PROTACs may be used in pharmaceutical compositions and methods for treating cell proliferative disorders associated with EZH2 activity, such as cancer.
1. A molecule having a formula: M EZH2 -L-M E3 or a salt, hydrate, or solvate thereof, wherein M EZH2 is a moiety that binds to EZH2, L is a bond or a linker covalently attaching M EZH2 and M E3 , and M E3 is a moiety that binds to an E3 ubiquitin ligase,
wherein M EZH2 has a formula:
wherein M E3 has a formula selected from:
2. The molecule of claim 1 , wherein L comprises a polyethylene glycol moiety, an alkylalkyne moiety, and/or an aminoalkyl alkyne moiety, or, wherein L has a formula selected from: —(CH 2 ) m —, —(CH 2 ) m CH 2 CH 2 C(O)NHCH 2 CH 2 —, —(CH 2 ) m CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 C(O)NHCH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 —, —(CH 2 ) m C(O)NHCH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 —, —CH 2 OCH 2 —, —CH 2 OCH 2 C(O)NHCH 2 CH 2 —, —CH 2 OCH 2 C(O)NHCH 2 CH 2 CH 2 —, —CH 2 OCH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, and —CH 2 OCH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, wherein m and n are 0-20.
3. A molecule having a formula: M EZH2 -L-M E3 or a salt, hydrate, or solvate thereof, wherein M EZH2 is a moiety that binds to EZH2, L is a bond or a linker covalently attaching M EZH2 and M E3 , and M E3 is a moiety that binds to an E3 ubiquitin ligase, wherein M EZH2 has a formula:
wherein M E3 has a formula selected from:
4. The molecule of claim 3 , wherein L comprises a polyethylene glycol moiety, an alkylalkyne moiety, and/or an aminoalkyl alkyne moiety, or, wherein L has a formula selected from: —(CH 2 ) m —, —(CH 2 ) m CH 2 CH 2 C(O)NHCH 2 CH 2 —, —(CH 2 ) m CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 C(O)NHCH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 —, —(CH 2 ) m C(O)NHCH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 —, —CH 2 OCH 2 —, —CH 2 OCH 2 C(O)NHCH 2 CH 2 —, —CH 2 OCH 2 C(O)NHCH 2 CH 2 CH 2 —, —CH 2 OCH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, and —CH 2 OCH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, wherein m and n are 0-20.
5. The molecule of claim 3 , wherein M E3 has a formula selected from:
6. The molecule of claim 3 , wherein M E3 has a formula:
7. A molecule having a formula: M EZH2 -L-M E3 or a salt, hydrate, or solvate thereof, wherein M EZH2 is a moiety that binds to EZH2, L is a bond or a linker covalently attaching M EZH2 and M E3 , and M E3 is a moiety that binds to an E3 ubiquitin ligase, wherein M EZH2 has a formula:
wherein M E3 has a formula selected from:
8. The molecule of claim 7 , wherein L comprises a polyethylene glycol moiety, an alkylalkyne moiety, and/or an aminoalkyl alkyne moiety, or, wherein L has a formula selected from: —(CH 2 ) m —, —(CH 2 ) m CH 2 CH 2 C(O)NHCH 2 CH 2 —, —(CH 2 ) m CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 C(O)NHCH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 —, —(CH 2 ) m C(O)NHCH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, —(CH 2 CH 2 O) n CH 2 CH 2 —, —CH 2 OCH 2 —, —CH 2 OCH 2 C(O)NHCH 2 CH 2 —, —CH 2 OCH 2 C(O)NHCH 2 CH 2 CH 2 —, —CH 2 OCH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, and —CH 2 OCH 2 C(O)NHCH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 —, wherein m and n are 0-20.
9. The molecule of claim 7 , wherein M E3 has a formula selected from:
10. The molecule of claim 7 , wherein M E3 has a formula:
11. A pharmaceutical composition comprising the molecule of claim 1 and a suitable pharmaceutical carrier, excipient, or diluent.
12. A pharmaceutical composition comprising the molecule of claim 3 and a suitable pharmaceutical carrier, excipient, or diluent.
13. A pharmaceutical composition comprising the molecule of claim 7 and a suitable pharmaceutical carrier, excipient, or diluent.