Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer

Zhang, Yan; Wu, Xishan; Xue, Xiaochang; Li, Chenchang; Wang, Junjian; Wang, Rui; Zhang, Cheng; Wang, Chao; Shi, Yudan; Zou, Lingjiao; Li, Qiu; Huang, Zenghong; Hao, Xiaojuan; Loomes, Kerry M.; Wu, Donghai; Chen, Hongwu; Xu, Jinxin; Xu, Yong

doi:10.1021/acs.jmedchem.9b00327

Cited by 37 publications

(29 citation statements)

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“…GSK805 was demonstrated to be effective in suppression of Th17 cell differentiation via antagonizing RORγt 26 , while XY018 was shown to strongly inhibit the growth of androgen receptor-positive prostate tumors via inhibition of tumor cell RORγ 27 . Both compounds displayed excellent selectivity toward RORγ 28 . We treated a panel of TNBC and ER+ human breast cancer cell lines and several mouse ER-negative cell lines with the two antagonists and two RORγ agonists along with the PARP-1 inhibitors (Fig.…”

Section: Resultsmentioning

confidence: 99%

RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

et al. 2019

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Tumor subtype-specific metabolic reprogrammers could serve as targets of therapeutic intervention. Here we show that triple-negative breast cancer (TNBC) exhibits a hyper-activated cholesterol-biosynthesis program that is strongly linked to nuclear receptor RORγ, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of RORγ reduces tumor cholesterol content and synthesis rate while preserving host cholesterol homeostasis. We demonstrate that RORγ functions as an essential activator of the entire cholesterol-biosynthesis program, dominating SREBP2 via its binding to cholesterol-biosynthesis genes and its facilitation of the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces chromatin acetylation at cholesterol-biosynthesis gene loci. RORγ antagonists cause tumor regression in patient-derived xenografts and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our study uncovers a master regulator of the cholesterol-biosynthesis program and an attractive target for TNBC.

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Section: Resultsmentioning

confidence: 99%

RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

et al. 2019

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“…RORγ expression is upregulated in prostate cancer and further increased in castration-resistant prostate cancer (CRPC). RORγ drives AR expression while selective RORγ antagonists inhibit AR expression and prostate tumor growth (Figure 1) [49,50], suggesting an oncogenic role for RORγ and its potential as a therapeutic target in prostate cancer. In contrast, an antioncogenic role for RORα in prostate cancer was indicated by its tumor suppression and anti-invasion functions [51,52].…”

Section: Subfamilies Of Nrsmentioning

confidence: 99%

The Role of Nuclear Receptors in Prostate Cancer

Shiota

Fujimoto

Kashiwagi

et al. 2019

Cells

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The nuclear receptor (NR) superfamily consists of 48 members that are divided into seven subfamilies. NRs are transcription factors that play an important role in a number of biological processes. The NR superfamily includes androgen receptor, which is a key player in prostate cancer pathogenesis, suggesting the functional roles of other NRs in prostate cancer. The findings on the roles of NRs in prostate cancer thus far have shown that several NRs such as vitamin D receptor, estrogen receptor β, and mineralocorticoid receptor play antioncogenic roles, while other NRs such as peroxisome proliferator-activated receptor γ and estrogen receptor α as well as androgen receptor play oncogenic roles. However, the roles of other NRs in prostate cancer remain controversial or uninvestigated. Further research on the role of NRs in prostate cancer is required and may lead to the development of novel preventions and therapeutics for prostate cancer.

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“…The crystal structure of human ATG4B (PDB code: 2CY7.pdb) downloaded from Protein Data Bank ( http://www.pdb.org ) was used for the molecular docking. The molecular docking was performed by Schrodinger program following our previous study [ 37 ]. The ligand and protein structure preparation, including water deletion, protonation-state adjustment, and hydrogen atoms and disulfide bonds adding were performed by Maestro (version 11.6.013, Schrödinger, LLC, New York, NY, 2018).…”

Section: Methodsmentioning

confidence: 99%

Targeting autophagy peptidase ATG4B with a novel natural product inhibitor Azalomycin F4a for advanced gastric cancer

Yang

Zhang

et al. 2022

Cell Death Dis

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Advanced gastric cancer (GCa) remains highly lethal due to the lack of effective therapies. Identifying promising therapeutic targets and developing effective treatment against GCa are urgently needed. Through mRNA and protein analysis of GCa clinical tumor samples, we found that autophagy-related gene 4B (ATG4B) was overexpressed in GCa tumors and that its high expression was associated with patients’ poor prognosis. Knockdown of ATG4B significantly inhibited GCa cell survival and tumor growth. To further probe the role of ATG4B in GCa by pharmacological means, we screened an in-house marine natural compound library against ATG4B and identified Azalomycin F4a (Am-F4a) as a novel and potent ATG4B inhibitor. Am-F4a directly bound to ATG4B with high affinity and effectively suppressed GCa cell autophagy via inhibition of ATG4B both in vitro and in vivo. Moreover, Am-F4a or ATG4B knockdown significantly suppressed tumor growth as well as GCa cell migration and invasion. Am-F4a effectively blocked the metastatic progression of primary GCa and sensitized tumors to chemotherapy. Taken together, our findings indicate that ATG4B is a potential therapeutic target against GCa and the natural product Am-F4a is a novel ATG4B inhibitor that can be further developed for the treatment of GCa.

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Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer

Cited by 37 publications

References 50 publications

RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

The Role of Nuclear Receptors in Prostate Cancer

Targeting autophagy peptidase ATG4B with a novel natural product inhibitor Azalomycin F4a for advanced gastric cancer

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