Abstract LB008: ATV-1601, a potent and selective allosteric inhibitor of AKT1E17K, demonstrates profound and durable regressions in multiple patient and cell derived xenograft models

Abstract Background: Hyperactive AKT signaling drives tumorigenesis across a wide swath of solid tumors. Of the three AKT isoforms, multiple lines of evidence point to AKT1 as the key isoform that drives tumorigenesis including genetic screens in PIK3CA/PTEN mutant cancer cell lines identifying AKT1 as a dependency, and an oncogenic gain-of-function mutation in the AKT1 Pleckstrin-Homology domain from glutamic acid to lysine (E17K). AKT1E17K driver mutations are predominantly found in ER+/HER2- breast cancer and also occur as a mechanism of acquired resistance to PIK3CAi treatment in these tumors. AKT1E17K mutations are also found in triple negative breast cancer, endometrial cancer, prostate cancer and other solid tumors. The therapeutic benefit of pan-AKT inhibitors have been well established in the clinic. However, pan-AKT inhibition has been shown to lead to a broad range of adverse events including hyperglycemia which is 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 that is highly selective against AKT2. 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 was used for lead optimization. Potency and selectivity were assessed in engineered BaF/3 cells dependent on AKT1E17K, AKT1 or AKT2. A PK/PD relationship was established in vivo using a CDX model. AKT1E17K target engagement was measured by phospho-AKT1E17K, and off-target activity was measured by phospho-AKT2, insulin and glucose levels. In vivo efficacy was assessed in cancer patient and cell xenograft (PDX/CDX) models. Results: In CDX models, ATV-1601 demonstrated a strong dose-proportional exposure and achieved >90% AKT1E17K inhibition for 24 hours without inhibition of AKT2. ATV-1601 demonstrated profound tumor regressions with long durations in ER+/HER2- and triple negative breast cancer and endometrial AKT1E17K PDX models. ATV-1601 also showed superior tumor growth inhibition in PIK3CA/PTEN mutant HR+/HER2- breast CDX models compared to Capivasertib due to its ability to inhibit wild-type AKT1 while maintaining selectivity against AKT2. Inhibition of AKT2 and subsequent hyperglycemia was not detected across multiple in vivo studies. Conclusion: ATV-1601 demonstrates exceptional efficacy with a favorable in vivo tolerability profile and the data support further advancing its development toward clinical studies. Citation Format: Shomit Sengupta, Aaron Coffin, Anna C. Schinzel, Christopher F. Bennett, Truc Pham, Benjamin F. Brigham, Gianna M. Iantosca, Rajiv G. Govindaraj, Joseph LaPointe, Joanne E. Prescott-Roy, William Church, Gordon Murray, Thomas Roddy, Anil K. Padyana, Marion Dorsch, Maria-Jesus Blanco. ATV-1601, a potent and selective allosteric inhibitor of AKT1E17K, demonstrates profound and durable regressions in multiple patient and cell derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB008.