Reference Detail

Ref Type Journal Article
PMID (27699769)
Authors Politz O, Siegel F, Bärfacker L, Bömer U, Hägebarth A, Scott WJ, Michels M, Ince S, Neuhaus R, Meyer K, Fernández-Montalván AE, Liu N, von Nussbaum F, Mumberg D, Ziegelbauer K
Title BAY 1125976, a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling-dependent tumor growth in mouse models.
Journal International journal of cancer
Vol 140
Issue 2
Date 2017 Jan 15
URL
Abstract Text The PI3K-AKT-mTOR signaling cascade is activated in the majority of human cancers, and its activation also plays a key role in resistance to chemo and targeted therapeutics. In particular, in both breast and prostate cancer, increased AKT pathway activity is associated with cancer progression, treatment resistance and poor disease outcome. Here, we evaluated the activity of a novel allosteric AKT1/2 inhibitor, BAY 1125976, in biochemical, cellular mechanistic, functional and in vivo efficacy studies in a variety of tumor models. In in vitro kinase activity assays, BAY 1125976 potently and selectively inhibited the activity of full-length AKT1 and AKT2 by binding into an allosteric binding pocket formed by kinase and PH domain. In accordance with this proposed allosteric binding mode, BAY 1125976 bound to inactive AKT1 and inhibited T308 phosphorylation by PDK1, while the activity of truncated AKT proteins lacking the pleckstrin homology domain was not inhibited. In vitro, BAY 1125976 inhibited cell proliferation in a broad panel of human cancer cell lines. Particularly high activity was observed in breast and prostate cancer cell lines expressing estrogen or androgen receptors. Furthermore, BAY 1125976 exhibited strong in vivo efficacy in both cell line and patient-derived xenograft models such as the KPL4 breast cancer model (PIK3CA(H1074R) mutant), the MCF7 and HBCx-2 breast cancer models and the AKT(E17K) mutant driven prostate cancer (LAPC-4) and anal cancer (AXF 984) models. These findings indicate that BAY 1125976 is a potent and highly selective allosteric AKT1/2 inhibitor that targets tumors displaying PI3K/AKT/mTOR pathway activation, providing opportunities for the clinical development of new, effective treatments.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
BAY1125976 BAY1125976 inhibits the activity of AKT1/2, which may result in reduced tumor cell proliferation and decreased growth of tumors with activated PI3K/AKT/mTOR signaling (PMID: 27699769).
Drug Name Trade Name Synonyms Drug Classes Drug Description
BAY1125976 Akt1 Inhibitor 5 Akt2 Inhibitor 2 BAY1125976 inhibits the activity of AKT1/2, which may result in reduced tumor cell proliferation and decreased growth of tumors with activated PI3K/AKT/mTOR signaling (PMID: 27699769).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
AKT1 E17K breast cancer sensitive BAY1125976 Preclinical - Pdx Actionable In a preclinical study, BAY1125976 induced complete tumor regression in a patient-derived xenograft (PDX) model of breast cancer harboring AKT E17K (PMID: 27699769). 27699769
AKT1 E17K anal canal cancer sensitive BAY1125976 Preclinical - Pdx Actionable In a preclinical study, treatment with BAY1125976 reduced tumor growth and resulted in partial tumor regression or stable disease in anal cancer patient-derived xenograft (PDX) models harboring AKT1 E17K (PMID: 27699769). 27699769 detail...
KRAS G12V PTEN K6fs prostate cancer sensitive BAY1125976 Preclinical - Cell culture Actionable In a preclinical study, BAY1125976 inhibited proliferation of a prostate cancer cell line harboring KRAS G12V and PTEN K6fs*4 in culture (PMID: 27699769). 27699769
PTEN T319fs breast cancer sensitive BAY1125976 Preclinical - Cell culture Actionable In a preclinical study, BAY1125976 inhibited proliferation of a breast cancer cell line harboring PTEN T319fs*1 in culture (PMID: 27699769). 27699769
PTEN L108R breast cancer sensitive BAY1125976 Preclinical - Cell culture Actionable In a preclinical study, BAY1125976 inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 27699769). 27699769
AKT1 E17K NRAS G12D prostate cancer sensitive BAY1125976 Preclinical - Cell line xenograft Actionable In a preclinical study, BAY1125976 inhibited proliferation of a prostate cancer cell line harboring AKT E17K and NRAS G12D in culture, and demonstrated antitumor activity in xenograft models (PMID: 27699769). 27699769