Discovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ) Agonist for Use in Treating Cancer

被引：21

作者：

Aicher, Thomas D. ^{[1
]}

Van Huis, Chad A. ^{[1
]}

Hurd, Alexander R. ^{[1
]}

Skalitzky, Donald J. ^{[1
]}

Taylor, Clarke B. ^{[1
]}

Beleh, Omar M. ^{[1
]}

Glick, Gary ^{[2
]}

Toogood, Peter L. ^{[1
]}

Yang, Bing ^{[3
]}

Zheng, Tao ^{[3
]}

Huo, Changxin ^{[3
]}

Gao, Jie ^{[3
]}

Qiao, Chenxi ^{[3
]}

Tian, Xiaolong ^{[3
]}

Zhang, Junping ^{[3
]}

Demock, Kellie ^{[4
]}

Hao, Ling-Yang ^{[4
]}

Lesch, Charles A. ^{[4
]}

Morgan, Rodney W. ^{[4
]}

Moisan, Jacques ^{[4
]}

Wang, Yahong ^{[4
]}

Scatina, JoAnn ^{[5
]}

Paulos, Chrystal M. ^{[6
]}

Zou, Weiping ^{[7
]}

Carter, Laura L. ^{[4
]}

Hu, Xiao ^{[4
]}

机构：

[1] Lycera Corp, Dept Chem, Ann Arbor, MI 48108 USA

[2] Lycera Corp, Ann Arbor, MI 48108 USA

[3] Pharmaron Beijing Co Ltd, Dept Chem, Beijing 100176, Peoples R China

[4] Lycera Corp, Dept Biol, Ann Arbor, MI 48108 USA

[5] Lycera Corp, Dept Preclin Dev, Plymouth Meeting, PA 19462 USA

[6] Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA

[7] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 18期

关键词：

CELL LUNG-CANCER; ANTITUMOR-ACTIVITY; T-CELLS; IMATINIB; DIFFERENTIATION; IDENTIFICATION; INHIBITION; ONCOLOGY; IMMUNITY; SURVIVAL;

D O I：

10.1021/acs.jmedchem.1c00731

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Retinoic acid receptor-related orphan receptor gamma (RORc, ROR gamma, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of ROR gamma(+) T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable smallmolecule ROR gamma agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.

引用

页码：13410 / 13428

页数：19

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