The PI3Kα/AKT/PTEN signaling pathway is one of the most frequently mutated and overactivated pathways in cancer, driving aggressive tumor growth in up to 70% of breast cancers—particularly hormone receptor-positive subtypes—and in 40–60% of prostate cancers through PTEN loss. Genetic alterations involving the pathway are also observed in a significant fraction of other solid tumors including NSCLC, ovarian, endometrial, head and neck, and bladder cancers.
Additionally, this pathway also plays a central role in genetic disorders such as Hereditary Hemorrhagic Telangiectasia (HHT), a disease marked by abnormal blood vessel formation that leads to severe nosebleeds, chronic anemia, organ damage, and a significantly reduced lifespan. Currently, there are no approved therapies for patients with HHT.
Among the three AKT isoforms (AKT1, AKT2, AKT3), AKT1 is a key regulatory protein in this pathway and is implicated as the dominant isoform in driving disease progression for both oncology and HHT. Preclinical studies show that selective AKT1 inhibition can regress tumors in breast, prostate, and other cancers, and prevent vascular malformations in HHT. In contrast, inhibiting AKT2 is linked to adverse effects such as rash and diabetes-like symptoms. While there has been considerable investment in pan-AKT inhibitors, these treatments are often limited by off-target toxicities—particularly due to AKT2—and the high structural similarity among AKT isoforms makes isoform-specific drug design challenging.
Terremoto Biosciences is developing a novel class of AKT1-selective inhibitors to overcome these limitations. Our approach aims to provide deeper and more durable target inhibition with an improved safety profile, resulting in more effective treatments for cancers and vascular overgrowth diseases like HHT that are driven by PI3Kα/AKT/PTEN dysregulation, addressing significant unmet medical needs.
