Potent, Selective, and Orally Bioavailable Inhibitors of Mammalian Target of Rapamycin (mTOR) Kinase Based on a Quaternary Substituted Dihydrofuropyrimidine

Cohen, Frederick; Bergeron, Philippe; Blackwood, Elizabeth M.; Bowman, Krista K.; Chen, Huifen; DiPasquale, Antonio G.; Epler, Jennifer; Koehler, Michael F. T.; Lau, Kevin; Lewis, Cristina; Liu, Lichuan; Ly, Cuong Q.; Malek, Shiva; Nonomiya, Jim; Ortwine, Daniel F.; Pei, Zhonghua; Robarge, Kirk; Sideris, Steve; Trinh, Lan; Truong, Tom; Wu, Jiansheng; Zhao, Xianrui; Lyssikatos, Joseph P.

doi:10.1021/jm200215y

Cited by 24 publications

(29 citation statements)

References 16 publications

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“…YL529 was also built and its geometry was optimized in Discovery Studio 2.55. The docking scheme was modified as described previously (Cohen et al ., ).…”

Section: Methodsmentioning

confidence: 97%

YL529, a novel, orally available multikinase inhibitor, potently inhibits angiogenesis and tumour growth in preclinical models

Lin

Meng

et al. 2013

British J Pharmacology

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Background and Purpose Targeted chemotherapy using small‐molecule inhibitors of angiogenesis and proliferation is a promising strategy for cancer therapy. Experimental Approach YL529 was developed via computer‐aided drug design, de novo synthesis and high‐throughput screening. The biochemical, pharmacodynamic and toxicological profiles of YL529 were investigated using kinase and cell viability assays, a mouse tumour cell‐containing alginate bead model, a zebrafish angiogenesis model and several human tumour xenograft models in athymic mice. Key Results In vitro, YL529 selectively inhibited the activities of VEGFR2/VEGFR3 and serine/threonine kinase RAF kinase. YL529 inhibited VEGF165‐induced phosphorylation of VEGFR2, as well as the proliferation, migration, invasion and tube formation of human umbilical vascular endothelial cells. It also significantly blocked vascular formation and angiogenesis in the zebrafish model. Moreover, YL529 strongly attenuated the proliferation of A549 cells by disrupting the RAF/mitogen‐activated protein (MAP) or extracellular signal‐regulated kinase (Erk) kinase (MEK) kinase kinase/MAPK pathway. Oral administration of YL529 (37.5–150 mg−1·kg−1·day−1) to nude mice bearing established tumour xenografts significantly prevented the growth (60–80%) of A549, SPC‐A1, A375, OS‐RC‐2 and HCT116 tumours without detectable toxicity. YL529 markedly reduced microvessel density and increased tumour cell apoptosis in the tumours formed in mice inoculated with the lung cancer cells, SPC‐A1 and A549, and the colon carcinoma cells, HCT116. Conclusions and Implications YL529, an orally active multikinase inhibitor, shows therapeutic potential for solid tumours, and warrants further investigation as a possible anticancer agent.

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“…YL529 was also built and its geometry was optimized in Discovery Studio 2.55. The docking scheme was modified as described previously (Cohen et al ., ).…”

Section: Methodsmentioning

confidence: 97%

YL529, a novel, orally available multikinase inhibitor, potently inhibits angiogenesis and tumour growth in preclinical models

Lin

Meng

et al. 2013

British J Pharmacology

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“…GDC-0980 (61), GDC-0941 (62), GNE-236 (63), and GDC-0068 (64) were synthesized at Genentech. AZD8055, sorafenib, axitinib, vandetanib, BEZ235, MK2206, selumetinib, and everolimus were purchased from Selleckchem or LC Laboratories.…”

Section: Reagentsmentioning

confidence: 99%

Phosphoproteomic Analysis Implicates the mTORC2-FoxO1 Axis in VEGF Signaling and Feedback Activation of Receptor Tyrosine Kinases

Zhuang¹,

Yu²,

Jiang³

et al. 2013

Sci. Signal.

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The vascular endothelial growth factor (VEGF) signaling pathway plays a pivotal role in normal development and also represents a major therapeutic target for tumors and intraocular neovascular disorders. The VEGF receptor tyrosine kinases promote angiogenesis by phosphorylating downstream proteins in endothelial cells. We applied a large-scale proteomic approach to define the VEGF-regulated phosphoproteome and its temporal dynamics in human umbilical vein endothelial cells and then used siRNA (small interfering RNA) screens to investigate the function of a subset of these phosphorylated proteins in VEGF responses. The PI3K (phosphatidylinositol 3-kinase)-mTORC2 (mammalian target of rapamycin complex 2) axis emerged as central in activating VEGF-regulated phosphorylation and increasing endothelial cell viability by suppressing the activity of the transcription factor FoxO1 (forkhead box protein O1), an effect that limited cellular apoptosis and feedback activation of receptor tyrosine kinases. This FoxO1-mediated feedback loop not only reduced the effectiveness of mTOR inhibitors at decreasing protein phosphorylation and cell survival but also rendered cells more susceptible to PI3K inhibition. Collectively, our study provides a global and dynamic view of VEGF-regulated phosphorylation events and implicates the mTORC2-FoxO1 axis in VEGF receptor signaling and reprogramming of receptor tyrosine kinases in human endothelial cells.

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“…Final compounds were tested in both mTOR and PI3K-α enzymatic assays, and inhibitory potency is reported as K i values. 11,12 Antiproliferative activities (reported as EC 50 values) were measured in a PC3 prostate cancer cell line, where the PI3K-AKt-mTOR pathway is activated via the loss of the tumor suppressor PTEN.…”

mentioning

confidence: 99%

“…6−10 We recently reported the discovery of potent, selective, ATPcompetitive mTOR inhibitors exemplified by compound 1 (Scheme 1). 11,12 interactions and potential toxicity, 13,14 we decided to identify compounds that are devoid of TDI. Here we report our efforts to improve the above properties while maintaining/improving the potency, leading to the discovery of a drug development candidate.…”

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confidence: 99%

Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349

Pei¹,

Blackwood²,

Liu³

et al. 2012

ACS Med. Chem. Lett.

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Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

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Potent, Selective, and Orally Bioavailable Inhibitors of Mammalian Target of Rapamycin (mTOR) Kinase Based on a Quaternary Substituted Dihydrofuropyrimidine

Cited by 24 publications

References 16 publications

YL529, a novel, orally available multikinase inhibitor, potently inhibits angiogenesis and tumour growth in preclinical models

YL529, a novel, orally available multikinase inhibitor, potently inhibits angiogenesis and tumour growth in preclinical models

Phosphoproteomic Analysis Implicates the mTORC2-FoxO1 Axis in VEGF Signaling and Feedback Activation of Receptor Tyrosine Kinases

Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349

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