Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799

Ohwada, Jun; Ebiike, Hirosato; Kawada, Hatsuo; Tsukazaki, Masao; Nakamura, Mariko; Miyazaki, Tatsuya; Morikami, Kenji; Yoshinari, Kiyoshi; Yoshida, Miyuki; Kondoh, Osamu; Kuramoto, Satoshi; Ogawa, Kotaro; Aoki, Yuko; Shimma, Nobuo

doi:10.1016/j.bmcl.2011.01.065

Cited by 62 publications

(44 citation statements)

References 10 publications

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“…In contrast to the positive role of the class III PI3K products in promoting autophagy, increases in the levels of class I PI3K products (phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-triphosphate) negatively regulate autophagy (46). Targeting this class I PI3K with inhibitors such as CH5132799, GDC-0980, and GDC-0941, leads to the activation of autophagy (47)(48)(49).…”

Section: R E V I E W S E R I E S : a U T O P H A G Y 9 Jciorgmentioning

confidence: 99%

Pharmacologic agents targeting autophagy

Vakifahmetoglu-Norberg¹,

Xia²,

Yuan³

2015

J. Clin. Invest.

207

177

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Section: R E V I E W S E R I E S : a U T O P H A G Y 9 Jciorgmentioning

confidence: 99%

Pharmacologic agents targeting autophagy

Vakifahmetoglu-Norberg¹,

Xia²,

Yuan³

2015

J. Clin. Invest.

207

177

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“…These data suggest a novel function for ceramide in autophagy upregulation. Recent studies show that CH5132799 [55] , GDC-0980 [56] , and GDC-0941 [57] potently inhibit signal transduction downstream of both PI3K and mTOR. However, only the pro-apoptotic mechanisms of these three novel class I PI3K inhibitors have been discussed.…”

Section: Class I Pi3k Inhibitorsmentioning

confidence: 99%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

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Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

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“…S1; ref. 19). The inhibitory effects of CH5132799 on PI3K kinase activity were examined in cell-free systems (Table 1).…”

Section: Ch5132799 Selectively Inhibited Class I Pi3k and Pi3ka Mutanmentioning

confidence: 99%

“…On the other hand, PI3K inhibitors are expected to block mTORC1 inhibition-induced Akt activation because PI3K acts upstream of Akt. We have previously identified the novel PI3K inhibitor CH5132799 (19).…”

Section: Introductionmentioning

confidence: 99%

The Selective Class I PI3K Inhibitor CH5132799 Targets Human Cancers Harboring Oncogenic PIK3CA Mutations

Tanaka¹,

Yoshida²,

Tanimura³

et al. 2011

Clinical Cancer Research

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Purpose: The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. PIK3CA mutations, which are found in many cancer patients, activate the PI3K pathway, resulting in cancer development and progression. We previously identified CH5132799 as a novel PI3K inhibitor. Thus, this study aimed to clarify the biochemical and antitumor activity of CH5132799 and elucidate the correlation between CH5132799 response and genetic alterations in the PI3K pathway.Experimental Design: Kinase inhibitory activity was profiled in cell-free assays. A large panel of human breast, ovarian, prostate, and endometrial cancer cell lines, as well as xenograft models, were used to evaluate the antitumor activity of CH5132799, followed by analysis for genetic alterations. Effects on Akt phosphorylation induced by mTORC1 inhibition were tested with CH5132799 and compared with mTORC1 and PI3K/mTOR inhibitors.Results: CH5132799 selectively inhibited class I PI3Ks and PI3Ka mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. In combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment.Conclusions: CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings. Clin Cancer Res; 17(10); 3272-81. Ó2011 AACR.

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Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799

Cited by 62 publications

References 10 publications

Pharmacologic agents targeting autophagy

Pharmacologic agents targeting autophagy

Application and interpretation of current autophagy inhibitors and activators

The Selective Class I PI3K Inhibitor CH5132799 Targets Human Cancers Harboring Oncogenic PIK3CA Mutations

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