"目录号: HY-15346
PI3K/Akt/mTOR-
BAY 80-6946 是一种 ATP竞争性的选择性 I 型PI3激酶抑制剂，作用于PI3Kα，PI3Kδ，PI3Kβ和PI3Kγ，IC50分别为 0.5，0.7，3.7 和 6.4 nM，作用于 mTOR，IC50为 45 nM。
PI3K
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生物活性
Description
BAY 80-6946 is an ATP-competitive selective class-IPI3kinases inhibitor, withIC50s of 0.5, 0.7, 3.7 and 6.4 nM forPI3Kα,PI3Kδ,PI3KβandPI3Kγ, and much less active against mTOR (IC50=45 nM) and other PIKs (no inhibition at 1 μM).
IC50& Target
IC50: 0.5 nM (PI3Kα), 0.7 nM (PI3Kδ), 3.7 nM (PI3Kβ), 6.4 nM (PI3Kγ)[1]
In Vitro
BAY 80-6946 potently inhibits the catalytic activity of the class I PI3Kα, β, γ, and δ isoforms with IC50s of 0.5, 3.7, 6.4, and 0.7 nM, respectively. BAY 80-6946 shows significantly weaker activity against mTOR with an IC50of 45 nM. In KPL4 cells, BAY 80-6946 reduces basal levels of AKT phosphorylation at both Thr308 and Ser473 with IC50values of 0.4 and 0.6 nM, respectively. BAY 80-6946 has mean IC50values of 19 nM against cell lines withPIK3CA-activating mutations (n = 9) and 17 nM against HER2-positive cell lines (n=7), whereas the activity inPIK3CAwild-type and HER2-negative cells is about 40-fold less potent (average IC50=774 nM; n=11)[2].
In Vivo
BAY 80-6946 is highly efficacious in a variety of human tumor xenograft models derived from different tumor indications that exhibit an activated PI3K pathway. BAY 80-6946 is administered at 0.5 to 6 mg/kg i.v. every second day for a total of five doses starting on day 14, following tumor cell implantation. On day 25, 3 days after the last dose, TGI rates of 77%, 84%, 99%, and 100% are observed with BAY 80-6946 at doses of 0.5, 1, 3, and 6 mg/kg, respectively. Complete tumor regression is shown in 10 of 10 rats in the 3 and 6 mg/kg groups, and all rats remained tumor free at the termination of the study on day 73. Tumor growth delays more than 25 days are observed in the 0.5 and 1 mg/kg dose groups[2].
Clinical Trial
NCT02369016
Bayer
Lymphoma, Non-Hodgkin
September 22, 2015
Phase 3
NCT02367040
Bayer
Lymphoma,Non-Hodgkin
August 3, 2015
Phase 3
NCT02626455
Bayer
Lymphoma, Non-Hodgkin
January 6, 2016
Phase 3
NCT01404390
Bayer
Neoplasms
August 2011
Phase 1
NCT01411410
Bayer
Neoplasms
August 2011
Phase 1
NCT00962611
Bayer
Neoplasms
November 2009
Phase 1
NCT01660451
Bayer
Lymphoma, Non-Hodgkin
November 19, 2012
Phase 2
NCT02253420
Bayer
Medical Oncology
October 8, 2014
Phase 1
NCT02391116
Bayer
Diffuse Large-Cell Lymphoma
May 8, 2015
Phase 2
NCT02155582
Bayer
Non Hodgkin Lymphoma
August 12, 2014
Phase 1
NCT02119221
Bayer
Healthy Volunteers
February 2014
Phase 1
NCT02342665
Bayer
Lymphoma Non-Hodgkin
April 21, 2015
Phase 1-Phase 2
NCT03172884
Bayer
Hepatic Insufficiency
June 14, 2017
Phase 1
NCT02455297
Bayer
Lymphoma, Mantle-Cell
August 2015
Phase 2
NCT01460537
Bayer
Neoplasms
November 2011
Phase 1
NCT02369016
Bayer
Lymphoma, Non-Hodgkin
September 22, 2015
Phase 3
NCT02367040
Bayer
Lymphoma,Non-Hodgkin
August 3, 2015
Phase 3
NCT02626455
Bayer
Lymphoma, Non-Hodgkin
January 6, 2016
Phase 3
NCT01404390
Bayer
Neoplasms
August 2011
Phase 1
NCT01411410
Bayer
Neoplasms
August 2011
Phase 1
NCT00962611
Bayer
Neoplasms
November 2009
Phase 1
NCT01660451
Bayer
Lymphoma, Non-Hodgkin
November 19, 2012
Phase 2
NCT02253420
Bayer
Medical Oncology
October 8, 2014
Phase 1
NCT02391116
Bayer
Diffuse Large-Cell Lymphoma
May 8, 2015
Phase 2
NCT02155582
Bayer
Non Hodgkin Lymphoma
August 12, 2014
Phase 1
NCT02119221
Bayer
Healthy Volunteers
February 2014
Phase 1
NCT02342665
Bayer
Lymphoma Non-Hodgkin
April 21, 2015
Phase 1-Phase 2
NCT03172884
Bayer
Hepatic Insufficiency
June 14, 2017
Phase 1
NCT02455297
Bayer
Lymphoma, Mantle-Cell
August 2015
Phase 2
NCT01460537
Bayer
Neoplasms
November 2011
Phase 1
NCT02822482
UNICANCER
Carcinoma, Squamous Cell of Head and Neck
June 2016
Phase 1-Phase 2
NCT03052933
Chonnam National University Hospital-Bayer-Consortium for Improving Survival of Lymphoma
Mature T-Cell and NK-Cell Neoplasm
May 2017
Phase 1-Phase 2
NCT02728258
NRG Oncology-National Cancer Institute (NCI)
Endometrial Endometrioid Adenocarcinoma-Endometrial Mixed Adenocarcinoma-Endometrial Serous Adenocarcinoma-Endometrial Undifferentiated Carcinoma-Metastatic Endometrioid Adenocarcinoma-PIK3CA Gene Mutation-Recurrent Uterine Corpus Carcinoma
September 2016
Phase 2
NCT02705859
Cancer Trials Ireland
HER2 Positive Breast Cancer
April 2016
Phase 1
NCT02631590
H. Lee Moffitt Cancer Center and Research Institute-Bayer
Biliary Carcinoma-Gall Bladder Carcinoma-Cholangiocarcinoma-Gastrointestinal Tumor
June 28, 2016
Phase 2
NCT03128619
Jonsson Comprehensive Cancer Center-National Cancer Institute (NCI)-Bayer
Estrogen Receptor Positive-HER2/Neu Negative-Invasive Breast Carcinoma-Multifocal Breast Carcinoma-Postmenopausal-Progesterone Receptor Positive-Stage I Breast Cancer-Stage IA Breast Cancer-Stage IB Breast Cancer-Stage II Breast Cancer-Stage IIA Breast Cancer-Stage IIB Breast Cancer-Stage III Breast Cancer-Stage IIIA Breast Cancer-Stage IIIB Breast Cancer-Stage IIIC Breast Cancer-Stage IV Breast Cancer
August 1, 2017
Phase 1-Phase 2
NCT01392521
Bayer
Neoplasms
July 2011
Phase 1
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References
[1].Will M, et al. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov. 2014 Mar;4(3):334-47.
[2].Liu N, et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol Cancer Ther. 2013 Nov;12(11):2319-30.