BYL-719

"目录号: HY-15244

PI3K/Akt/mTOR-

BYL-719 是一种有效的选择性PI3Kα抑制剂，IC50为 5 nM。

PI3K

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

NCT03207529

M.D. Anderson Cancer Center-Novartis-Astellas Pharma Global Development, Inc.

Malignant Neoplasm of Breast

August 2017

Phase 1

NCT02624557

Novartis Pharmaceuticals-Novartis

Hepatic Impairment

December 21, 2015

Phase 1

NCT02437318

Novartis Pharmaceuticals-Novartis

Breast Cancer

July 23, 2015

Phase 3

NCT03056755

Novartis Pharmaceuticals-Novartis

Breast Cancer

July 15, 2017

Phase 2

NCT02620839

Pamela Munster-University of California, San Francisco

Solid Tumors

December 1, 2016

Phase 1

NCT02077933

Novartis Pharmaceuticals-Novartis

Neoplasms-Breast Neoplasms-Kidney Neoplasms-Pancreatic Neuroendocine Neoplasms

May 2014

Phase 1

NCT02058381

Novartis Pharmaceuticals-Novartis

Pre-menopausal Breast Cancer-PI3K Pathway Inhibition

May 6, 2014

Phase 1

NCT02273219

Richard D. Carvajal-Columbia University

Uveal Melanoma

November 2014

Phase 1

NCT02051751

Novartis Pharmaceuticals-Novartis

Neoplasms, Breast Neoplasms, Head and Neck Neoplasms

March 5, 2014

Phase 1

NCT01219699

Novartis Pharmaceuticals-Novartis

Advanced Solid Tumors With an Alteration of the PIK3CA Gene-Estrogen Receptor Positive Breast Cancer

October 5, 2010

Phase 1

NCT01449058

Array BioPharma

Advanced and Selected Solid Tumors, AML, High Risk and Very High Risk MDS

March 2012

Phase 1-Phase 2

NCT01623349

Dana-Farber Cancer Institute-Novartis-AstraZeneca

Ovarian Cancer-Breast Cancer

September 2012

Phase 1

NCT01791478

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

NCT02282371

Memorial Sloan Kettering Cancer Center-Novartis Pharmaceuticals

Head and Neck Squamous Cell Cancer

October 2014

Phase 1

NCT01928459

Novartis Pharmaceuticals-Novartis

Advanced Solid Tumors-Metastatic Solid Tumors

October 2013

Phase 1

NCT01735968

Novartis Pharmaceuticals-Novartis

3rd Line GIST

February 2013

Phase 1

NCT01870505

Memorial Sloan Kettering Cancer Center-Novartis Pharmaceuticals

Metastatic or Locally-advanced Unresectable Breast Cancer

May 2013

Phase 1

NCT02038010

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

NCT01613950

Novartis Pharmaceuticals-Novartis

Stomach Neoplasms Esophageal Neoplasms Metastatic Gastric Cancer Mutated PI3KCA Protein Overexpressed HER2 Protein

December 2012

Phase 1

NCT01387321

Novartis Pharmaceuticals-Novartis

Advanced Solid Tumor

September 2011

Phase 1

NCT02167854

Memorial Sloan Kettering Cancer Center-Novartis

Breast Cancer

June 16, 2014

Phase 1

NCT02379247

University of Kansas Medical Center-Novartis Pharmaceuticals

Breast Cancer

February 2015

Phase 1-Phase 2

NCT01708161

Novartis Pharmaceuticals-NantCell, Inc.-Novartis

PIK3CA Mutated Advanced Solid Tumors-PIK3CA Amplified Advanced Solid Tumors

November 27, 2012

Phase 1-Phase 2

NCT02145312

Yonsei University

Recurrent or Metastatic Squamous Cell Carcinoma of Head and Neck

October 2016

Phase 2

NCT02144038

Novartis Pharmaceuticals-Novartis

Relapsed and Refractory Multiple Myeloma

July 2014

Phase 1-Phase 2

NCT02155088

H. Lee Moffitt Cancer Center and Research Institute-Novartis

Pancreatic Cancer

October 30, 2014

Phase 1

NCT03138070

Lawson Health Research Institute

Head and Neck Squamous Cell Cancer

May 2017

NCT01602315

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

NCT01719380

Array BioPharma

Colorectal Cancer

November 2012

Phase 1-Phase 2

NCT02550743

howard safran-Brown University-Lifespan-Novartis Pharmaceuticals Corporation (Financial supporter)

Rectal Cancer

June 2016

Phase 1