EEDi-5285: An Exceptionally Potent, Efficacious, and Orally Active Small-Molecule Inhibitor of Embryonic Ectoderm Development

被引：26

作者：

Rej, Rohan Kalyan ^{[4
,5
]}

Wang, Changwei ^{[4
,5
]}

Lu, Jianfeng ^{[4
,5
]}

Wang, Mi ^{[4
,5
]}

Petrunak, Elyse ^{[6
]}

Zawacki, Kaitlin P. ^{[4
,5
]}

McEachern, Donna ^{[4
,5
]}

Fernandez-Salas, Ester ^{[4
,5
]}

Yang, Chao-Yie ^{[4
,5
]}

Wang, Lu ^{[4
,7
]}

Li, Ruiting ^{[4
,7
]}

Chinnaswamy, Krishnapriya ^{[6
]}

Wen, Bo ^{[4
,7
]}

Sun, Duxin ^{[4
,7
]}

Stuckey, Jeanne ^{[4
,6
]}

Zhou, Yunlong ^{[8
]}

Chen, Jianyong ^{[8
]}

Tang, Guozhi ^{[8
]}

Wang, Shaomeng ^{[1
,2
,3
]}

机构：

[1] Univ Michigan, Dept Internal Med, Med Sch, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Pharmacol, Med Sch, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Coll Pharm, Dept Med Chem, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Life Sci Inst, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA

[8] Ascentage Pharma Grp, Suzhou 215216, Jiangsu, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 13期

关键词：

POLYCOMB REPRESSIVE COMPLEX; PRC2; EZH2; LYMPHOMA;

D O I：

10.1021/acs.jmedchem.0c00479

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of embryonic ectoderm development (EED) is a new cancer therapeutic strategy. Herein, we report our discovery of EEDi-5285 as an exceptionally potent, efficacious, and orally active EED inhibitor. EEDi-5285 binds to the EED protein with an IC50 value of 0.2 nM and inhibits cell growth with IC50 values of 20 pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively, carrying an EZH2 mutation. EEDi-5285 is approximately 100 times more potent than EED226 in binding to EED and >300 times more potent than EED226 in inhibition of cell growth in the KARPAS422 cell line. EEDi-5285 has excellent pharmacokinetics and achieves complete and durable tumor regression in the KARPAS422 xenograft model in mice with oral administration. The cocrystal structure of EEDi-5285 in a complex with EED defines the precise structural basis for their high binding affinity. EEDi-5285 is the most potent and efficacious EED inhibitor reported to date.

引用

页码：7252 / 7267

页数：16

共 33 条

[31] Development of an orally-administrative MELK (maternal embryonic leucine zipper kinase)-targeting small molecule inhibitor that suppresses the growth of various types of human cancer.
Chung, Suyoun
Suzuki, Hanae
Miyamoto, Takashi
Takamatsu, Naofumi
Tatsuguchi, Ayako
Ueda, Koji
Kijima, Kyoko
Matsuo, Yo
Nakamura, Yusuke
CANCER RESEARCH, 2013, 73 (08)
[32] Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity
Dorr, P
Westby, M
Dobbs, S
Griffin, P
Irvine, B
Macartney, M
Mori, J
Rickett, G
Smith-Burchnell, C
Napier, C
Webster, R
Armour, D
Price, D
Stammen, B
Wood, A
Perros, M
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2005, 49 (11) : 4721 - 4732
[33] ANTI-TUMOR ACTIVITY OF CB-668, A POTENT, SELECTIVE AND ORALLY BIOAVAILABLE SMALL-MOLECULE INHIBITOR OF THE IMMUNO-SUPPRESSIVE ENZYME INTERLEUKIN 4 (IL-4)-INDUCED GENE 1 (IL4I1)
MacKinnon, Andrew
Bhupathi, Deepthi
Chen, Jason
Huang, Tony
Li, Weiqun
Ma, Yong
Sotirovska, Natalija
Steggerda, Susanne
Zhang, Winter
Parlati, Francesco
JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2020, 8 : A423 - A424

← 1 2 3 4 →