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Compromised PTEN function is associated with multiple cancers. As per the continuum model, variable degree of PTEN inactivation drives distinct cancer phenotypes. Loss of PTEN activity, via genomic/non-genomic mechanisms, leads to enhanced oncogenic PI3K signaling. While kinase inhibitors have proved effective in the clinic, they are increasingly met with off-target effects and therapy-resistance due to compensatory feedback mechanisms. Although PTEN restoration therapy has proved promising in experimental models; implementation of these therapies in the clinic remains challenging. To fill this therapy gap, we have targeted endogenous PTEN for activation via peptidomimetics, mitigating PI3K signaling. Our selected peptidomimetics reduced cell proliferation, migration and cell cycle activity after treatment of non-small cell lung cancer cells expressing endogenous PTEN. Computational studies utilizing PTEN crystal structures revealed a binding site at the interface of the Phosphatase Domain (PD) and C2 Domain (C2D). Induced fit docking indicated that a unique functional group is responsible for peptidomimetic-mediated enhancement of PTEN activity. Molecular dynamics analysis revealed energetically favorable binding of our lead peptidomimetic at the PD/C2D interface, which allosterically modulated the conformation of the active site. Binding of our peptidomimetic altered the active site orientation of PIP3, increasing its binding affinity. In summary, we have developed the first-known direct PTEN activators and analyzed their effects in suppressing oncogenic activities in lung cancer. Refinement of our peptidomimetics, complemented with in vivo studies, will provide a novel clinical rationale to reduce doses of standard therapy and their associated toxicities, decreasing morbidity and mortality observed in the clinic. Citation Format: Emily Palumbo, Peng Teng, Prerna Malaney, Jacob Wilson, Fiona Kearns, Michael T. Kemp, Zhi Tian, Vladimir Uversky, Diane Allen-Gipson, Yu Chen, H. Lee Woodcock, Jianfeng Cai, Vrushank Dave. Enhancement of PTEN activity via peptidomimetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4826.