Abstract P5-04-24: ATV-1601 is a Potent and Selective Allosteric Inhibitor of AKT1E17K and Shows Profound and Durable Regressions in AKT1E17K-Driven Patient Derived Xenograft Models

作者：Shomit Sengupta, Anna C. Schinzel, Aaron R. Coffin, Truc Le-Buu Pham, Benjamin Brigham, Gianna M. Iantosca, Rajiv G. Govindaraj, Joseph H. LaPointe, Joann Prescott-Roy, David N. Church, Gordon J. Murray, Thomas P. Roddy, Anil K. Padyana, Marion Dorsch, Marı́a-Jesús Blanco · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1557-3265.sabcs24-p5-04-24 · 研究领域：Eicosanoids and Hypertension Pharmacology

Abstract Background: The AKT pathway modulates cell survival and proliferation in response to insulin and growth factor signaling. A gain-of-function mutation in the AKT1 Pleckstrin-Homology domain from glutamic acid to lysine (E17K) leads to constitutive activation resulting in tumorigenesis. AKT1E17K driver mutations are predominantly found in ER+/HER2- breast cancer and occur as a mechanism of acquired resistance to PIK3CAi treatment in these tumors. Additionally, AKT1E17K mutations are found in triple negative breast cancer, endometrial cancer, prostate cancer and meningiomas among other solid tumors. The therapeutic benefit of inhibiting the AKT/PI3K pathway has been well established in the clinic. However, AKT/PI3K pathway inhibition has been shown to lead to a broad range of adverse events including hyperglycemia, which in the case of pan-AKT inhibitors is primarily driven by inhibition of AKT2. To maximize tolerability and efficacy in AKT1E17K mutant patients, we have developed ATV-1601, a novel orally bioavailable, non-covalent, allosteric AKT1E17K inhibitor. Methods: ATV-1601 was developed using structure-based drug design and driven by incorporating molecular interactions observed between AKT1E17K and mutant-selective metabolite binders discovered using Atavistik’s proprietary Atavistik Metabolite-Protein Screening (AMPS) technology. A combination of biophysical, biochemical, and cell-based methods were used for lead optimization. Potency and selectivity were asses...