The mammalian target of rapamycin (mTOR) is a highly conserved Ser/Thr protein kinase and a central controller of cell growth, proliferation, and survival. Studies have linked the hyperactive PI3K-AKT-mTOR signaling pathway in a variety of human cancers. Drugs targeting to PI3K and mTOR are likely to be an effective treatment for human malignancies that rely on these targets for their growth. Institute of Pharmaceutics at Development Center for Biotechnology in Taiwan has developed a novel and potent small molecule DCBCI0901 as PI3K/mTORC1/mTORC2 inhibitor. DCBCI0901 attenuated cell survival and proliferation in both in vitro and in vivo models. DCBCI0901 possessed IC50 of 8.4 nM against mTOR kinase and IC50 of 78 nM against PI3Kα (p110α/p85α) while exerting high selectivity against a panel of 20 other serine/ threonine and tyrosine kinases. In addition, DCBCI0901 is highly active in cellular assays. It causes a significant reduction in phospho-p70S6K (mTORC1 substrate), phospho-AKT (S473) (mTORC2 substrate), and phospho-AKT (T308) (PI3K substrate) levels. The antitumor efficacy of DCBCI0901 was evaluated in diverse human tumor cell lines. DCBCI0901 effectively inhibits cell proliferation of five well-established cell lines (one NSCLC, A549; two prostate cancers, PC-3 and LNCap; two breast cancers, HCC1954 and BT474), with IC50 values ranging from 6 to 48 nM. Notably, DCBCI0901 is effective against a panel of nine lung cancer cell lines (one cell line is EGFR-TKI sensitive model and eight cell lines are EGFR-TKI resistant model), with IC50 in the ten of nanomolar range. DCBCI0901 showed significant antitumor efficacy in mouse xenograft models including lung cancer, prostate cancer, and leukemia with tumor growth inhibition greater than 65%. DCBCI0901 also demonstrated effective suppression of tumor growth in advanced-stage xenograft models (lung cancer (A549), mean tumor volume > 350mm3 at the start of treatment). Furthermore, in an EGFR-TKI resistant lung cancer H1975 xenograft model, DCBCI0901 effectively suppressed tumor growth. Based on the in vitro/in vivo pharmacology data, DCBCI0901 was selected as a drug candidate for further development as anticancer agent.
This publication is dedicated to the memory of Dr. Paonien Chen.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C270.
Citation Format: Ying-Shuan E. Lee, Mann-Yan Kuo, Yi-Ting Huang, Yu-Wen Tseng, Yu Jie Lin, Yen His Liu, Shian-Yi Chiou, Li Jung Chen, Y.-Y. Lu, Chih-Hsin Yang, Pan-Chyr Yang. In vitro and in vivo antitumor activity of DCBCI0901, a potent PI3K/mTORC1/mTORC2 inhibitor. [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 C270.