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	Vol	Issue	Date	Pages	Journal Short Title
International journal of cancer	140	2	2017 Jan 15	449-459	Int J Cancer

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 (PIK3CAH1074R mutant), the MCF7 and HBCx-2 breast cancer models and the AKTE17K 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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
BAY1125976	BAY1125976	9	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BAY1125976		BAY 1125976\|BAY-1125976	Akt1 Inhibitor 7 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, PMID: 31835495).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
PIK3CA	R1023Q	missense	unknown	PIK3CA R1023Q lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). R1023Q has been identified in the scientific literature (PMID: 27699769, PMID: 36620501, PMID: 24092809), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Mar 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
PIK3CA P539R	breast cancer	sensitive	BAY1125976	Preclinical - Cell culture	Actionable	In a preclinical study, BAY1125976 inhibited proliferation of a breast cancer cell line harboring PIK3CA P539R in culture (PMID: 27699769).	27699769
PIK3CA H1047R	breast cancer	sensitive	BAY1125976	Preclinical - Cell line xenograft	Actionable	In a preclinical study, BAY1125976 inhibited proliferation of breast cancer cell lines harboring PIK3CA H1047R in culture, and inhibited AKT signaling and tumor growth in a PIK3CA H1047R-mutant cell line xenograft model (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
PIK3CA H1047R PTEN E307K	breast cancer	sensitive	BAY1125976	Preclinical - Cell culture	Actionable	In a preclinical study, BAY1125976 inhibited proliferation of a breast cancer cell line harboring PIK3CA H1047R and PTEN E307K in culture (PMID: 27699769).	27699769
PIK3CA E545K	breast cancer	sensitive	BAY1125976	Preclinical - Cell line xenograft	Actionable	In a preclinical study, BAY1125976 inhibited proliferation of a breast cancer cell line harboring PIK3CA E545K in culture, and inhibited AKT signaling and tumor growth in xenograft models (PMID: 27699769).	27699769
PIK3CA K111N	breast cancer	sensitive	BAY1125976	Preclinical - Cell culture	Actionable	In a preclinical study, BAY1125976 inhibited proliferation of a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 27699769).	27699769