Targeting the PI3K-AKT-mTOR Pathway: The Potential of BAY 1125976 in Cancer Therapy

The PI3K/AKT/mTOR signaling pathway is often dysregulated in cancer, with AKT playing a crucial role in tumorigenesis and being implicated in resistance to various cancer therapies. BAY 1125976 is a novel, allosteric inhibitor of AKT1/2, showing promise in preclinical studies for its potential use in treating cancers with PI3K-AKT pathway alterations.

BAY 1125976 has exhibited high selectivity and potency against AKT1 and AKT2, with low nanomolar IC50 values, and weaker activity against AKT3. It is inactive against a broad panel of other kinases. The inhibitor targets the phosphorylation of AKT at key sites, Thr308 and Ser473, and downstream signaling, as evidenced by the inhibition of 4E-BP1 phosphorylation. This leads to a significant suppression of tumor cell proliferation in vitro, particularly in cell lines with PTEN loss or PIK3CA mutations.

In human xenograft tumor models, daily oral administration of BAY 1125976 has induced robust pharmacodynamic effects, inhibiting AKT phosphorylation in correlation with drug levels. The compound has also shown dose-dependent antitumor effects in multiple xenograft models, with tumors harboring PIK3CA mutations or PTEN deletions, and has been well-tolerated.

Furthermore, BAY 1125976 can be combined with different anticancer treatments, showing synergistic anti-proliferative effects when paired with anti-hormonal therapies in breast and prostate cancer cell lines. This synergy translated to enhanced antitumor efficacy and durable tumor regressions in vivo. The combination of BAY 1125976 with radiation therapy has demonstrated strong additive to synergistic effects, leading to significant delays in tumor growth.

Additionally, the combination of BAY 1125976 with the bone-targeting agent Radium 223 in a breast cancer bone metastasis model has resulted in a reduction of tumor and metastatic burden, along with an increase in necrotic and fibrotic bone areas.

In summary, BAY 1125976 is a highly selective AKT1/2 inhibitor with significant in vitro and in vivo activity against tumors with activated AKT signaling. It also shows strong potential when combined with other therapies, suggesting that targeting AKT could be a valuable strategy for overcoming resistance to chemotherapy and radiation and for enhancing the effectiveness of these treatments.