Abstract 6360: Development of a new substituted 1,3-dioxoisoindoline series that are RPS6K1 protein kinase inhibitors as potential cancer therapeutics

Abstract

Abstract The 40S ribosomal S6 kinase 1 (S6K1), a conserved serine/threonine protein kinase, is the principal kinase effector downstream of the PI3K/mTOR regulatory signaling pathway. Over-expression of RPS6K1 has been associated with cell transformation and elevated proliferation rates in tumors, poor prognosis and an increased risk of local recurrence. RPS6K1 has been found to play an important role in the progression of ER-positive breast cancer, HER2 positive breast cancer and node-negative premenopausal breast cancer. Overexpression of RPS6K1 is closely correlated with aggressive progression and poor prognosis in prostate cancer patients. Inhibition of this kinase can prove to be beneficial for the treatment of several types of cancer including breast cancer, prostate cancer, non-small cell lung cancer, etc. Our laboratory has identified 7-amino-5-amido-1,3-dioxoisoindolines as S6K1 inhibitors with low micromolar IC50 values (2-5 μM). These compounds also inhibited the growth of prostate cancer cells DU-145 and breast cancer cells MCF-7 (ER-positive) and SKBR3 (HER2-positive). The IC50 values of growth inhibition of SKBR3 breast cancer cell lines by the compounds RJ19, RJ22 and RJ28 are 3.3, 1.9 and 4.7 μM, respectively. The core structure 5,7-diamino-1,3-dioxoisoindoline was found to selectively inhibit RPS6K1 over 99 other oncologic protein kinases. This series of compounds have the potential to become viable therapeutics for many types of cancer. The results from the synthesis of 7-amino-5-amido-1,3-dioxoisoindoline derivatives, the structure activity studies, and their efficacy studies will be presented. Citation Format: Jayalakshmi Sridhar, Rajesh Komati, Melyssa Bratton. Development of a new substituted 1,3-dioxoisoindoline series that are RPS6K1 protein kinase inhibitors as potential cancer therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6360.