IP Library › Granted Patent US 12,491,252
Granted Patent B2
US 12,491,252 · App. 18/747,376 · Granted Dec 9, 2025

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

Inventors: Gary E. Schiltz (Naperville, IL); Jindan Yu (Evanston, IL)
Assignee: Northwestern University
A61K47/55A61K47/545A61P35/00
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Quick Facts
Patent No.
US 12,491,252
App. No.
18/747,376
Granted
Dec 9, 2025
Kind
B2
Abstract

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.

Claims (24)

1 . A method of treating cancer, the method comprising administering a composition comprising a molecule having a formula: M EZH2 -L-M E3 or a salt, hydrate, or solvate thereof, and a suitable pharmaceutical carrier, excipient, or diluent to a subject having the cancer, 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 the cancer is selected from prostate cancer and lymphoma,

wherein M EZH2 has a formula:

 and

wherein M E3 has a formula selected from:

2 . The method 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.

3 . A method of treating cancer, the method comprising administering a composition comprising a molecule having a formula: M EZH2 -L-M E3 or a salt, hydrate, or solvate thereof, and a suitable pharmaceutical carrier, excipient, or diluent to a subject having the cancer, 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 the cancer is selected from prostate cancer and lymphoma,

wherein M EZH2 has a formula:

 und

wherein M E3 has a formula selected from:

4 . The method 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 method of claim 3 , wherein M E3 has a formula selected from:

6 . The method of claim 3 , wherein M E3 has a formula:

7 . A method of treating cancer, the method comprising administering a composition comprising a molecule having a formula: M EZH2 -L-M E3 or a salt, hydrate, or solvate thereof, and a suitable pharmaceutical carrier, excipient, or diluent to a subject having the cancer, 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 the cancer is selected from prostate cancer and lymphoma,

wherein M EZH2 has a formula:

 and

wherein M E3 has a formula selected from:

8 . The method 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 method of claim 7 , wherein M E3 has a formula selected from:

10 . The method of claim 7 , wherein M E3 has a formula:

11 . The method of claim 1 , wherein M E3 has a formula selected from:

12 . The method of claim 1 , wherein M E3 has a formula:

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 13, 2025
From: SCHILTZ, GARY E.; YU, JINDAN
To: NORTHWESTERN UNIVERSITY
Reel/Frame 069835/0186 →
CONFIRMATORY LICENSE Recorded Sep 13, 2024
From: NORTHWESTERN UNIVERSITY
To: UNITED STATES GOVERNMENT
Reel/Frame 068954/0113 →
Continuity (3)
Division 17735003 · May 2, 2022
Provisional Application 63201459 · Apr 30, 2021
Related Publication 20240335546A1 · Oct 10, 2024
References Cited (34)
US 20180085465A1 · Bradner et al. · 2018 [cited by applicant]
US 20180134684A1 · Bradner et al. · 2018 [cited by applicant]
US 20180186785A1 · Crews et al. · 2018 [cited by applicant]
US 20180327419A1 · Bradner et al. · 2018 [cited by applicant]
US 20190016703A1 · Gray et al. · 2019 [cited by applicant]
US 20190071415A1 · Bradner et al. · 2019 [cited by applicant]
US 20190076539A1 · Phillips et al. · 2019 [cited by applicant]
US 20190076540A1 · Phillips et al. · 2019 [cited by applicant]
US 20190076541A1 · Phillips et al. · 2019 [cited by applicant]
US 20190076542A1 · Phillips et al. · 2019 [cited by applicant]
US 20190106417A1 · Gray et al. · 2019 [cited by applicant]
US 20190151295A1 · Crew et al. · 2019 [cited by applicant]
US 20190151457A1 · Bradner et al. · 2019 [cited by applicant]
US 20190194190A1 · Yang et al. · 2019 [cited by applicant]
US 20190255041A1 · Jin et al. · 2019 [cited by applicant]
US 20190262502A1 · Garcia-Gareta et al. · 2019 [cited by applicant]
US 20190263798A1 · Harling et al. · 2019 [cited by applicant]
US 20190275161A1 · Heightman et al. · 2019 [cited by applicant]
US 20200022966A1 · Tang et al. · 2020 [cited by applicant]
US 20200085817A1 · Jaenisch et al. · 2020 [cited by applicant]
US 20200102298A1 · Gray et al. · 2020 [cited by applicant]
US 20200140456A1 · Phillips et al. · 2020 [cited by applicant]
Cancer [online], [retrieved on Jul. 6, 2007] Retrieved from the Internet, URL: http://www.nim.nih.gov/medlineplus/cancer.html (Year: 2007). [cited by examiner]
Lala et al., Role of nitric oxide in tumor progression: Lessons from experimental tumors, Cancer and Metastasis Reviews (1998), 17 , 91-106 (Year: 1998). [cited by examiner]
Golub et al., Molecular Classification of Cancer: Class Discovery and Class Prediction by Gene Expression Monitoring, Science (1999), vol. 286, 531-537 (Year: 1999). [cited by examiner]
An et al., “Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs,” EBioMedicine. Oct. 2018; 36: 553-562. [cited by applicant]
Gu et al., “PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery,” Bioessays. Apr. 2018; 40(4):e1700247. [cited by applicant]
Kong, et al., “Astemizole Arrests the Proliferation of Cancer Cells by Disrupting the EZH2-EED Interaction of Polycomb Repressive Complex 2,” J. Med. Chem. 2014, 57(22), 9512-9521. [cited by applicant]
Knutson, S. K, et al., “Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma,” Mol. Cancer Ther. (2014) 13(4):842-54. [cited by applicant]
He, et al., “Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors,” Bioorganic & Medicinal Chemistry Letters, 30(5), 126957; 2020. [cited by applicant]
Qi, et al., “An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED,” Nat. Chem. Bio. 2017, 13, 381-388. [cited by applicant]
Lin, et al., “Discovery of Potent and Selective Covalent Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors,” ACS Med. Chem. Lett. 2019, 10, 334. [cited by applicant]
Ma, et al., “Discovery of a first-in-class EZH2 selective degrader,” Nat Chem Biol. 2020, 16, 214. [cited by applicant]
Kuntz, et al., “The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat,” J. Med. Chem. 2016, 59, 1556. [cited by applicant]