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| 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. | ||||||||||||
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| 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. | ||||||||||||
| 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, Feb 2025). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| 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 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 |
| 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 |
| 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 | 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 |
| 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 |