Author: Tang, Guozhi ; Stuckey, Jeanne A. ; Wang, Mi ; Rej, Rohan Kalyan ; Zawacki, Kaitlin P. ; Yang, Chao-Yie ; Chinnaswamy, Krishnapriya ; Wang, Lu ; Lu, Jianfeng ; Petrunak, Elyse ; Wen, Bo ; Li, Ruiting ; Wang, Changwei ; Sun, Duxin ; Zhou, Yunlong ; Wang, Shaomeng ; Chen, Jianyong ; McEachern, Donna

Embryonic ectoderm development (EED) is a promising therapeutic target for human cancers and other diseases. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded exceptionally potent EED inhibitors. The best compound EEDi-5273 binds to EED with an IC₅₀ value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC₅₀ value of 1.2 nM. It demonstrates an excellent PK and ADME profile, and its oral administration leads to complete and persistent tumor regression in the KARPAS422 xenograft model with no signs of toxicity. Co-crystal structures of two potent EED inhibitors with EED provide a solid structural basis for their high-affinity binding. EEDi-5273 is a promising EED inhibitor for further advanced preclinical development for the treatment of human cancer and other human diseases.

09 Jul 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Wang, Shaomeng ; Zhou, Yunlong ; Tang, Guozhi ; Wang, Mi ; Fernandez-Salas, Ester ; Wang, Lu ; Li, Ruiting ; Rej, Rohan Kalyan ; Wen, Bo ; Stuckey, Jeanne ; Zawacki, Kaitlin P. ; Chen, Jianyong ; Yang, Chao-Yie ; Petrunak, Elyse ; McEachern, Donna ; Chinnaswamy, Krishnapriya ; Wang, Changwei ; Sun, Duxin ; Lu, Jianfeng

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.

Chinese Journal of Structural Chemistry

Docking and 3D-QSAR studies on the imidazo[1,5-c]pyrimidine Derivative as EED Inhibitors

Author: Chen, Xiao-Zhong ; Shen, Yan ; Li, Guang-Ping ; Lin, Zhi-Hua ; Wang, Juan ; Hu, Yong ; Wang, Yuan-Qiang

Embryonic ectoderm development (EED) has become a novel target for cancer treatment.In this study, a series of EED inhibitors was subjected to a three-dimensional quant. structure-activity relationship (3D-QSAR) and mol. docking.Accordingly, this is the first of such 3D-QSAR studies in a series of EED inhibitors displaying anti-cancer pharmacol. profiles.The CoMFA (q² = 0.792, r² = 0.994, r²pred = 0.74) and CoMSIA (q² = 0.873, r² = 0.994, r²pred = 0.81) models demonstrated good robustness and predictive ability.Moreover, mol. docking suggested that cation-π,π-π stacking and hydrogen bonding interactions were the main factors affecting the activity of these inhibitors.Five new small mols. were designed based on the CoMFA and CoMSIA contour maps.These mols. were then submitted to further ADME studies, in which the ADME properties of the five designed mols. were found to be within a reasonable range.In view of the corresponding findings, this study may provide theor. guidance for the rational design of novel EED inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	-	University of Michigan	-

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