Abstract 789: CT413 is a novel dual Axl/Mer inhibitor that potently inhibited the growth of Axl overexpressed tumors
Authors: Xi Ning , Wang Tingjin , Wu Yanjun , Liao Min , Feng Yanming , Kang Ning , Wang Zhaohe , Zhang Yingjun 
Published: August 2015

Receptor tyrosine kinases (RTKs), which play an important role in cell signal transduction, are proven therapeutic targets for the treatment of human cancers. Axl and Mer are members of the TAM family which also includes Tyro-3. Axl has been established as a strong drug target candidate for therapeutic inhibition of cancer invasion and dissemination. As metastatic disease is the most frequent cause of cancer patient mortality, therapeutics specifically aimed at inhibiting metastatic dissemination and colonization would be important additions to the arsenal of drugs in clinical use. Some FDA-approved or in clinical trial molecules block Axl and Mer activity, however, there is no inhibitor clearly designed to inhibit Axl and Mer on the market. As a potential new therapy against malignant tumor, the development of Axl and Mer dual inhibitors is of great significance.

CT413 is a novel, orally bioavailable Axl/Mer inhibitor that is currently in our preclinical development pipeline. In biochemical assay, CT413 potently inhibit Axl and Mer with respective IC50 values of 4 and &lt; 1 nM. Among 97 kinase screened, CT413 inhibited Met and Ron receptor tyrosine kinases with IC50 values of 3 and 9 nM, respectively. Furthermore, CT413 blocked the Axl, Met and Ron autophosphorylation in cells with IC50 values of 13, 34 and 540 nM, respectively, demonstrating high kinase selectivity in both biochemical and cell-based assays. CT413 potently suppressed tumor growth in BALB/cA-nu/nu mice bearing subcutaneous human tumor xenografts. For example, in A549 (NSCLC), SK-OV-3 (ovarian) and K562 (CML) tumor models, CT413 inhibited tumor growth with TGIs of 84%, 110% and 66% dosed orally at 30 mg/kg QD, as compared to the vehicle-treated group. CT413 did not inhibit CYP450 subtype 3A4, 2D6, 1A2, 2C9 and 2C19 (IC50 &gt; 10 μM) and showed no induction effect on CYP450 subtype 1A2, 2B6 and 3A4. Furthermore, the IC50 of CT413 at hERG sodium ion channel was determined to be greater than 30 μM, indicating its minimal cardio-liability. CT413 exhibited good metabolic stability when incubated with human or rat microsome. Pharmacokinetic studies performed in rodents and large animals showed that CT413 had low clearance and high oral exposures across animal species. The oral bioavailability for mice, rats, dogs and monkeys are 133%, 85%, 83% and 68% respectively. The non-GLP 28-day toxicity studies in rats and dogs indicated that CT413 has an excellent therapeutic window. Based on these promising results, CT413 is advanced in our project pipeline as a clinical candidate for cancer therapy.

Citation Format: Ning Xi, Tingjin Wang, Yanjun Wu, Min Liao, Yanming Feng, Ning Kang, Zhaohe Wang, Yingjun Zhang. CT413 is a novel dual Axl/Mer inhibitor that potently inhibited the growth of Axl overexpressed tumors. [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 789. doi:10.1158/1538-7445.AM2015-789