Abstract 2659: Discovery of CT365, a highly potent inhibitor of PI3K and mTOR, for cancer treatment
Authors: Xi Ning , Wu Yanjun , Wang Tingjin , Wang Heng , Li Zhiyong , Meng Qingwei , Li Jing , Wang Zhaohe , Zhang Yingjun 
Published: August 2015

The Phosphatidylinositol 3-kinase (PI3K) regulates essential cellular functions including cell metabolism, growth, migration, survival and angiogenesis. PI3K are divided into three subclasses on the basis of structure, regulation and lipid substrate specificity. The class I subgroup of PI3K, which includes class IA isoforms α, β, δ and class IB isoform γ, is involved primarily in the pathogenesis of human cancer. Thus, activation of the PI3K/AKT/mTOR pathway is commonly observed in human cancer and is critical for tumor progression and resistance to anti-neoplastic drugs, including cytotoxic chemotherapy and targeted drugs. Agents targeted at PI3K/mTOR signaling pathway are believed useful to treat proliferative diseases such as cancers and pulmonary fibrosis. PI3K/mTOR dual inhibitors have enhanced efficacy and a favorable safety profile. With increased understanding of immune modulation, better strategic application of rational combinations, and greater focus on patient selection, this promising class of targeted agents may soon be able to realize its potential to treat human cancers.

Our clinical candidate CT365 is a potent, orally bioavailable small molecule kinase inhibitor against class I subgroup PI3Ks and mTOR. In the biochemical assays, CT365 exhibited nanomolar activities against human PI3 kinase p110α/p85α, p110β/p85α, p110δ/p85αand p120γ, with respective IC50 values of 4, 41, 2, and 6 nM. It also inhibited mTOR with an IC50 of 4 nM. CT365 demonstrated high degree of kinase selectivity when CT365 was profiled in the KinomeScan platform against a panel of 97 kinases, with only 3 kinases showing less than 10% of control binding at 1 μM. CT365 potently suppressed tumor growth in human tumor subcutaneous xenograft models with ED50s in the range of 0.8 ∼ 1.5 mg/kg. In pharmacokinetic analysis, clearance in mice, rats, dogs and cynomolgus monkeys was 0.33, 4.83, 4.50 and 2.67 mL/min/kg; and oral bioavailability in mice, rats, dogs and monkeys was 79, 95, 108 and 60%, respectively. CT365 showed no inhibition against CYP450 subtypes 3A4, 2D6, 1A2, 2C9 and 2C19 at 10 μM and no induction at 1A2, 2B6 and 3A4. The IC50 at hERG sodium channel was also determined to be greater than 30 μM. Non-GLP 28-day toxicological studies in mice and dogs indicated that CT365 has good therapeutic window. Based on the remarkable potencies of CT365 in both in vitro and in vivo studies, and desirable pharmacokinetic and toxicological profiles, CT365 was selected as a clinical candidate for the treatment of cancer.

Citation Format: Ning Xi, Yanjun Wu, Tingjin Wang, Heng Wang, Zhiyong Li, Qingwei Meng, Jing Li, Zhaohe Wang, Yingjun Zhang. Discovery of CT365, a highly potent inhibitor of PI3K and mTOR, for cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2659. doi:10.1158/1538-7445.AM2015-2659