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BYL-719 Chemical Structure
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BYL719 is an orally bioavailable phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antineoplastic activity.
PI3K inhibitor BYL719 specifically inhibits PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway, thereby inhibiting the activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents
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Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation.
Phosphatidylinositol-3-kinase α (PI3Kα) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2-aminothiazole compounds in inhibiting PI3Kα, a medicinal chemistry program has led to the discovery of the clinical candidate NVP-BYL719
Abstract CT-01: BYL719, a next generation PI3K alpha specific inhibitor: Preliminary safety, PK, and efficacy results from the first-in-human study
Cancer Research: April 15, 2012; Volume 72, Issue 8, Supplement 1
Introduction: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is implicated in many human cancers. Until recently, drugs that specifically inhibit the alpha isoform of PI3K that is activated by alterations in the PIK3CA gene have been missing. BYL719 is the first oral PI3K inhibitor that strongly and selectively inhibits the PI3K alpha isoform of PI3K. Its biological activity correlates with inhibition of various downstream signaling components of the PI3K/Akt pathway and it inhibits the proliferation of breast cancer cell lines harboring PIK3CA mutations. In vivo, BYL719 shows statistically significant dose-dependent anti-tumor efficacy in PIK3CA mutant xenograft models in rodents. Methods: BYL719 entered clinical investigation in 2010 exclusively in patients (pts) with advanced solid malignancies carrying an alteration in the PIK3CA gene. In the dose escalation phase, dose selection is guided by a Bayesian regression model with overdose control. As of 21-Sep-2011, a total of 25 pts with a variety of solid tumors, such as colon and breast cancer, have been enrolled and treated at once daily oral doses ranging from 30mg to 450mg. Results: The safety profile of the compound is characterized by mostly on-target toxicity, such as hyperglycemia (33% of pts), which was found more frequently at higher doses and is largely reversible with BYL719 interruption and treatment with oral anti-diabetics. Other commonly reported toxicities include nausea (38%) and decreased appetite, diarrhea, and vomiting (each 29%). 2 DLTs of hyperglycemia and nausea, both CTCAE grade 3, were observed in 2 pts out of 5 treated at 450mg/d. In humans, BYL719 has a low clearance, a half-life of 8.5 h and its exposure increases dose proportionally between 30mg/d and 450mg/d, displaying a low inter-individual variability in Cmax and AUC. Exposure levels reached at clinical doses above 270 mg/d correspond to exposures causing tumor stasis or regression in preclinical PIK3CA dependent xenograft models. First signs of clinical efficacy of BYL719 include 1 confirmed partial response in a patient with ER+ breast cancer treated at 270mg/d. In addition, preliminary data suggest that significant PET responses (PMR) and/or tumor shrinkage were achieved in 8 out of 17 evaluated pts. Three pts had prolonged stable disease (≥7 months) at doses below 270mg/d and overall 8 patients have been on the study for at least 4 months. Upon determination of the MTD for the once daily dosing regimen, ~45 pts with PIK3CA altered solid tumors will be enrolled into a safety expansion arm. Also, the PK and MTD for twice daily administration of BYL719 will be investigated. Conclusion: The preliminary clinical data available so far suggest BYL719 to be well tolerated, and showing signs of clinical activity, with manageable side effects and a predictable PK profile.
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