Discovery and Development of SPR519 as a Potent, Selective, and Orally Bioavailable Inhibitor of PI3Kα and mTOR Kinases for the Treatment of Solid Tumors

Q1 · MEDICINE

Article

Author: Kuila, Bilash ; Dugar, Sundeep ; Gawade, Lalita Babasaheb ; Sagar, Milind ; Arora, Reena ; Mahajan, Dinesh ; Sharma, Amit ; Sen, Somdutta ; Mahapatra, Amal Ray

Herein, we report the identification and preclinical profile of a lead compound 10, (SPR519) as an equally potent dual inhibitor of PI3Kα and mTOR kinases. SPR519 exhibits an EC₅₀ of low sub-micromolar range among various tested cancer cell lines such as A2780 (0.23 μM), PC3 (0.48 μM), and SKOV3 (0.50 μM). When administrated orally, it shows a considerably high plasma exposure (area under curve: 26,858 nM/h at 1 mg/kg) in mice. Moreover, it is found to be safe in animals with a dose of 30 mg/kg BID for 12 days in the dose tolerance study. SPR519 did not show any CYP or hERG liability. The identified lead compound demonstrates significant efficacy and bioavailability in ovarian and colon cancer xenograft models when evaluated for dose-ranging efficacy studies, at a dose as low as 2.5 mg/kg.

Frontiers in OncologyQ3 · MEDICINE

SPR965, a Dual PI3K/mTOR Inhibitor, as a Targeted Therapy in Ovarian Cancer

Q3 · MEDICINE

ArticleOA

Author: Chan, Leo Li-Ying ; Sullivan, Stephanie A ; Fang, Ziwei ; Sun, Wenchuan ; Dugar, Sundeep ; Bae-Jump, Victoria ; Zhou, Chunxiao ; Yin, Yajie ; Tran, Arthur-Quan

SPR965 is an inhibitor of PI3K and mTOR C1/C2 and has demonstrated anti-tumorigenic activity in a variety of solid tumors. We sought to determine the effects of SPR965 on cell proliferation and tumor growth in human serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer (KpB model) and identify the underlying mechanisms by which SPR965 inhibits cell and tumor growth. SPR965 showed marked anti-proliferative activity by causing cell cycle arrest and inducing cellular stress in ovarian cancer cells. Treatment with SPR965 significantly inhibited tumor growth in KpB mice, accompanied by downregulation of Ki67 and VEGF and upregulation of Bip expression in ovarian tumors. SPR965 also inhibited adhesion and invasion through induction of the epithelial–mesenchymal transition process. As expected, downregulation of phosphorylation of AKT and S6 was observed in SPR965-treated ovarian cancer cells and tumors. Our results suggest that SPR965 has significant anti-tumorigenic effects in serous ovarian cancer in vitro and in vivo. Thus, SPR965 should be evaluated as a promising targeted agent in future clinical trials of ovarian cancer.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	India	Sphaera Pharma Pvt Ltd.	-

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