DS[[Unable to Display Character: ‑]]3078a is a potent, selective small molecule inhibitor of the catalytic site of the mammalian target of rapamycin (mTOR). Our previous study showed DS-3078a to inhibit mTOR kinase activity in a concentration-dependent manner with an IC50 (concentration resulting in 50% of maximum inhibition) of approximately single digit nano molar. Here the antitumor potency of DS-3078a against various cancer cell lines in vitro and in vivo is shown. DS-3078a was applied to a 230 cell line panel assay to evaluate cell growth inhibition and apoptosis induction activity. In this study, DS-3078a was found to be a highly cytostatic compound with strong cell growth inhibiting activity. DS-3078a exhibited GI50s lower than 500 nM against over 200 cell lines and a 5-fold and higher caspase activation against only 36 cell lines. Among 12 in vivo xenograft models, 9 of 12 xenograft models demonstrated greater than a 50% tumor growth inhibition response at half of MTD dosing. There are several well-known selective mTOR kinase inhibitors including AZD8055 and OSI-027. When comparing the cellular response among these compounds, DS-3078a was found to have a weaker induction of the sub G1 population against AN3 CA human endometrial carcinoma cell line than the other two compounds, despite its similar kinase inhibiting profile against them. In a previous study, an increase of the phospho Akt(T308) by DS-3078a treatment in A498 human renal cell carcinoma, which was a sign of negative feedback loop disruption by inhibition of mTORC1 was demonstrated. In this model, AZD8055 and OSI-027 did not increase phospho Akt(T308), which implies inhibition of the PI-3K signal at higher concentrations. To understand the impact of the cytostatic characteristics of DS-3078a, in vivo mTOR signal inhibition at MTD using tumor bearing mouse was measured and compared to the signal inhibition pattern of AZD8055 and the PI-3K/mTOR dual inhibitor DS-7423. DS-3078a fully inhibited mTORC1 and mTORC2 downstream signals for 24 hr, while signal inhibition by DS-7423 was reduced by 18 hr. AZD8055 showed a similar pattern to DS-7423 at MTD dosing. This study highlights the unique characteristics of DS-3078a which may offer a unique differentiation of response and toxic profile compared to other mTOR inhibiting compounds in the clinical setting.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B184.

Citation Format: Kenichi Wakita, Masaki Kiga, Noriko Togashi. In vitro and in vivo profiling of novel mTORC1/2 inhibitor DS-3078a. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B184.