Antitumor Activity of ZSTK474, a New Phosphatidylinositol 3-Kinase Inhibitor

Yaguchi, Shin‐ichi; Fukui, Yoshihiro; Koshimizu, Ichiro; Haga, Yoshimi; Matsuno, Tetsuya; Gouda, Hiroaki; Hirono, Shuichi; Yamazaki, Kanami; Yamori, Takao

doi:10.1093/jnci/djj133

Cited by 361 publications

(297 citation statements)

References 42 publications

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“…Recently, it has been shown that a pan-class IA PI3K inhibitor ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], which was originally developed as an anticancer drug, (53) has a suppressive effect on inflammation and osteoclasts in collageninduced arthritis model, (54) suggesting that inhibition of class IA PI3K is a promising strategy for the rheumatoid arthritis therapy.…”

Section: Discussionmentioning

confidence: 99%

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Shirakawa

Nakamura

Masuda

et al. 2012

Journal of Bone and Mineral Research

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Class IA phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptors and regulate a wide range of cellular processes. In osteoclasts, they are activated downstream of a v b 3 integrin and colony-stimulating factor-1 receptor (c-Fms), which are involved in the regulation of bone-resorbing activity. The physiological relevance of the in vitro studies using PI3K inhibitors has been of limited value, because they inhibit all classes of PI3K. Here, we show that the osteoclast-specific deletion of the p85 genes encoding the regulatory subunit of the class IA PI3K results in an osteopetrotic phenotype caused by a defect in the bone-resorbing activity of osteoclasts. Class IA PI3K is required for the ruffled border formation and vesicular transport, but not for the formation of the sealing zone. p85a/b doubly deficient osteoclasts had a defect in macrophage colony-stimulating factor (M-CSF)-induced protein kinase B (Akt) activation and the introduction of constitutively active Akt recovered the bone-resorbing activity. Thus, the class IA PI3K-Akt pathway regulates the cellular machinery crucial for osteoclastic bone resorption, and may provide a molecular basis for therapeutic strategies against bone diseases. ß

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Section: Discussionmentioning

confidence: 99%

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Shirakawa

Nakamura

Masuda

et al. 2012

Journal of Bone and Mineral Research

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“…In conclusion, the ongoing clinical evaluation on these PI3K inhibitors is expected to furnish a new class of molecular targeted anticancer drugs. [11] . (C) Lineweaver-Burk plot analysis of inhibition of PI3Kα by ZSTK474 [64] .…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, ZSTK474 inhibited the growth of 39 human cancer [11] , ( Figure 4A) and blocked cell cycle progression at G 0 /G 1 phase in various human cancer cells without obvious induction of apoptosis [11,66] . The G 0 /G 1 arrest effect might be attributed to inactivation of cyclin D1, enhanced expression of p27, and the following pRB dephosphorylation [66] .…”

Section: Pi3k a Promising Molecular Target For Cancer Chemo Therapymentioning

confidence: 97%

“…COMPARE analysis was then carried out by comparing the fingerprint of ZSTK474 with those of other antitumor drugs and chemical tools that have known molecular targets in the JFCR39 drug-activity database. Intriguingly, a high r value of 0.766 was found between the fingerprint of ZSTK474 and that of LY294002, a classical PI3K inhibitor [11] . Therefore, we predicted that ZSTK474 might also be a PI3K inhibitor.…”

Section: Pi3k a Promising Molecular Target For Cancer Chemo Therapymentioning

confidence: 97%

“…To investigate the specificity of ZSTK474 as a PI3K inhibitor, we examined its inhibition against 139 known protein kinases [11] . As a result, no potent inhibition was shown even at a high concentration of ZSTK474 (30 µmol/L).…”

Section: Pi3k a Promising Molecular Target For Cancer Chemo Therapymentioning

confidence: 99%

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ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

Kong

Yamori

2010

Acta Pharmacol Sin

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JFCR39 is an informatic anticancer drug discovery system that utilizes a panel of 39 human cancer cells coupled with a drug-activity database. This system not only provides disease-oriented information but can also predict the mechanism of action of a given antitumor agent. Development of a phosphatidylinositol 3-kinase (PI3K) inhibitor as an anticancer drug candidate has attracted a great deal of attention from both academia and industry because PI3K is known to be closely involved in carcinogenesis. ZSTK474 was identified as a PI3K inhibitor using JFCR39 system in combination with COMPARE analysis program. These findings were based on the similar fingerprint (growth inhibition profiles for JFCR39 human cancer cell line panel) with that of a classical PI3K inhibitor LY294002. Biochemical experiments confirmed ZSTK474 to be a potent pan-class I PI3K inhibitor, with high selectivity over other classes of PI3K and protein kinases. We previously reported the in vitro and in vivo antitumor efficacy of ZSTK474, together with the G 0 /G 1 arrest and antiangiogenic activity. Here, we review the JFCR39 system and summarize recent studies on PI3K biology and the development of PI3K inhibitors before discussing ZSTK474 in some detail.

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Rational Drug Design of Small Molecule Anticancer Agents: Early Clinical Development

Molife¹,

Collins²,

Workman³

et al. 2007

The Cancer Handbook

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There has been a significant increase in the understanding of the molecular changes leading to malignant transformation, and cancer scientists and physicians are now at the dawn of another era in cancer therapeutics. The identification of new drug targets and potential biomarkers, and the development of molecular targeted therapies for use in oncology are moving rapidly forward. It is imperative that appropriate and speedy advances in clinical trial design accommodate these developments, as the traditional design of early phase trials for ‘standard’ anti‐cancer therapies may not necessarily be appropriate for these new agents. In this chapter, we discuss some of the challenges posed in early clinical development of novel targeted therapies. These include the redefining of trial endpoints such as maximum tolerated dose, dose limiting toxicity and radiological response and applying new concepts such as novel clinical trial design, maximum biological dose, use of surrogate tissue as a biomarker for drug effect, and prolonged disease stasis as a measure of clinical benefit. We review clinical studies of several classes of small molecule anticancer therapies to illustrate attempts to maximise the benefits of these non traditional methodologies and minimise the limitations in driving the field of molecular cancer therapeutics further forward.

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Antitumor Activity of ZSTK474, a New Phosphatidylinositol 3-Kinase Inhibitor

Abstract: ZSTK474 is a new PI3K inhibitor with strong antitumor activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.

Cited by 361 publications

References 42 publications

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

Rational Drug Design of Small Molecule Anticancer Agents: Early Clinical Development

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