"目錄號: HY-15244
BYL-719 是一種有效的選擇性PI3Kα抑制劑，IC50為 5 nM。
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生物活性
Description
BYL-719 is a potent and selectivePI3Kαinhibitor withIC50of 5 nM.
IC50& Target
IC50: 5 nM (p110α), 250? nM (p110γ), 290? nM (p110δ), 1200? nM (p110β)[1]
In Vitro
BYL-719 (NVP-BYL719) potently inhibits the 2 most common PIK3CA somatic mutations (H1047R, E545K; IC50~4 nM). BYL-719 potently inhibits Akt phosphorylation in cells transformed with PI3Kα (IC50=74±15 nM) and shows significant reduced inhibitory activity in PI3Kβ or PI3Kδ isoforms transformed cells (≥15-fold compared with PI3Kα)[2]. BYL-719 (BYL719) decreases cell proliferation by blocking cell cycle in G0/G1phase with no outstanding effects on apoptosis cell death in HOS and MOS-J tumor cells. BYL-719 inhibits cell migration and can thus be considered as a cytostatic drug for osteosarcoma. In murine preclinical models of osteosarcoma, BYL-719 significantly decreases tumor progression and tumor ectopic bone formation as shown by a decrease of Ki67+cells and tumor vascularization. BYL-719 rapidly inhibits the levels of P-AKT and P-mTOR in all cell lines assessed, confirming the functional activity of BYL-719 on osteosarcoma cells. After 72 hr of treatment, BYL-719 significantly inhibits the cell growth of all osteosarcoma cell lines tested in a dose-dependent manner with an IC50ranging from 6 to 15 μM and with the IC90from 24 to 42 μM at 72 hr[3].
In Vivo
BYL-719 displays excellent oral bioavailability in rats, mice and dogs and does not show any significant inhibition of the CYP450 enzymes[1]. BYL-719 (BYL719) inhibits tumor growth in pre-clinical murine models of osteosarcoma. C57Bl/6J with MOS-J tumors (n=6 per group) are randomized as controls (vehicle) or BYL-719 (12.5 mg/kg or 50 mg/kg per day)[3].
Clinical Trial
M.D. Anderson Cancer Center-Novartis-Astellas Pharma Global Development, Inc.
Malignant Neoplasm of Breast
August 2017
Phase 1
Novartis Pharmaceuticals-Novartis
Hepatic Impairment
December 21, 2015
Phase 1
Novartis Pharmaceuticals-Novartis
Breast Cancer
July 23, 2015
Phase 3
Novartis Pharmaceuticals-Novartis
Breast Cancer
July 15, 2017
Phase 2
Pamela Munster-University of California, San Francisco
Solid Tumors
December 1, 2016
Phase 1
Novartis Pharmaceuticals-Novartis
Neoplasms-Breast Neoplasms-Kidney Neoplasms-Pancreatic Neuroendocine Neoplasms
May 2014
Phase 1
Novartis Pharmaceuticals-Novartis
Pre-menopausal Breast Cancer-PI3K Pathway Inhibition
May 6, 2014
Phase 1
Richard D. Carvajal-Columbia University
Uveal Melanoma
November 2014
Phase 1
Novartis Pharmaceuticals-Novartis
Neoplasms, Breast Neoplasms, Head and Neck Neoplasms
March 5, 2014
Phase 1
Novartis Pharmaceuticals-Novartis
Advanced Solid Tumors With an Alteration of the PIK3CA Gene-Estrogen Receptor Positive Breast Cancer
October 5, 2010
Phase 1
Array BioPharma
Advanced and Selected Solid Tumors, AML, High Risk and Very High Risk MDS
March 2012
Phase 1-Phase 2
Dana-Farber Cancer Institute-Novartis-AstraZeneca
Ovarian Cancer-Breast Cancer
September 2012
Phase 1
Vanderbilt-Ingram Cancer Center-National Cancer Institute (NCI)
Estrogen Receptor-positive Breast Cancer-HER2-negative Breast Cancer-Invasive Ductal Breast Carcinoma-Progesterone Receptor-positive Breast Cancer-Recurrent Breast Cancer-Stage IV Breast Cancer
April 2013
Phase 1
Memorial Sloan Kettering Cancer Center-Novartis Pharmaceuticals
Head and Neck Squamous Cell Cancer
October 2014
Phase 1
Novartis Pharmaceuticals-Novartis
Advanced Solid Tumors-Metastatic Solid Tumors
October 2013
Phase 1
Novartis Pharmaceuticals-Novartis
3rd Line GIST
February 2013
Phase 1
Memorial Sloan Kettering Cancer Center-Novartis Pharmaceuticals
Metastatic or Locally-advanced Unresectable Breast Cancer
May 2013
Phase 1
Northwestern University-Novartis-National Cancer Institute (NCI)
HER2-positive Breast Cancer-Recurrent Breast Cancer-Stage IIIA Breast Cancer-Stage IIIB Breast Cancer-Stage IIIC Breast Cancer-Stage IV Breast Cancer
February 2014
Phase 1
Novartis Pharmaceuticals-Novartis
Stomach Neoplasms Esophageal Neoplasms Metastatic Gastric Cancer Mutated PI3KCA Protein Overexpressed HER2 Protein
December 2012
Phase 1
Novartis Pharmaceuticals-Novartis
Advanced Solid Tumor
September 2011
Phase 1
Memorial Sloan Kettering Cancer Center-Novartis
Breast Cancer
June 16, 2014
Phase 1
University of Kansas Medical Center-Novartis Pharmaceuticals
Breast Cancer
February 2015
Phase 1-Phase 2
Novartis Pharmaceuticals-NantCell, Inc.-Novartis
PIK3CA Mutated Advanced Solid Tumors-PIK3CA Amplified Advanced Solid Tumors
November 27, 2012
Phase 1-Phase 2
Yonsei University
Recurrent or Metastatic Squamous Cell Carcinoma of Head and Neck
October 2016
Phase 2
Novartis Pharmaceuticals-Novartis
Relapsed and Refractory Multiple Myeloma
July 2014
Phase 1-Phase 2
H. Lee Moffitt Cancer Center and Research Institute-Novartis
Pancreatic Cancer
October 30, 2014
Phase 1
Lawson Health Research Institute
Head and Neck Squamous Cell Cancer
May 2017
Novartis Pharmaceuticals-Novartis
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma-Recurrent Head and Neck Squamous Cell Carcinoma-Metastatic Head and Neck Squamous Cell Carcinoma
November 2012
Phase 1-Phase 2
Array BioPharma
Colorectal Cancer
November 2012
Phase 1-Phase 2
howard safran-Brown University-Lifespan-Novartis Pharmaceuticals Corporation (Financial supporter)
Rectal Cancer
June 2016
Phase 1
University Health Network, Toronto-Novartis Pharmaceuticals
Squamous Cell Carcinoma of Head and Neck-Locoregionally Advanced
September 2015
Phase 1
Novartis Pharmaceuticals-Novartis
Breast Cancer
October 22, 2013
Phase 1
Novartis Pharmaceuticals-Novartis
Esophageal Squamous Cell Carcinoma
July 26, 2013
Phase 1
Novartis Pharmaceuticals-Novartis
Breast Cancer
May 2014
Phase 1-Phase 2
Novartis Pharmaceuticals-Novartis
Breast Cancer
March 11, 2014
Phase 2
Novartis Pharmaceuticals-Novartis
Advanced or Metastatic ER+ Breast Cancer
April 27, 2016
Phase 1
Julie E. Bauman, MD, MPH-Novartis-University of Pittsburgh
Carcinoma, Squamous-Squamous Cell Carcinoma-Oropharyngeal Neoplasms-Oropharyngeal Cancer
August 2016
Phase 1-Phase 2
Novartis Pharmaceuticals-Novartis
Adenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma
January 20, 2015
Phase 2
Peter MacCallum Cancer Centre, Australia-Novartis Pharmaceuticals
Metastatic Breast Cancer
July 2015
Phase 2
UNC Lineberger Comprehensive Cancer Center-Novartis Pharmaceuticals
Metastatic Breast Cancer
August 2011
Phase 1
M.D. Anderson Cancer Center-Novartis-Astellas Pharma Global Development, Inc.
Malignant Neoplasm of Breast
August 2017
Phase 1
Novartis Pharmaceuticals-Novartis
Hepatic Impairment
December 21, 2015
Phase 1
Novartis Pharmaceuticals-Novartis
Breast Cancer
July 23, 2015
Phase 3
Novartis Pharmaceuticals-Novartis
Breast Cancer
July 15, 2017
Phase 2
Pamela Munster-University of California, San Francisco
So
