BAY 80-6946

"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.