Centaurus Biopharma Co Ltd

Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling.Significance: CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia. Cancer Res; 78(14); 3995–4006. ©2018 AACR.

CT-707, a mutant-selective inhibitor of an important cancer target, anaplastic lymphoma kinase (ALK), is designed to be a targeted therapeutic agent for non-small cell lung cancer (NSCLC) patients harboring ALK active and crizotinib resistant mutations. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of CT-707 and its two metabolites (M1 and M2) in human plasma. The samples were purified by solid phase extraction (SPE) and separated on a BEH C18 column (2.1 × 50 mm, 1.7 μm). Electrospray ionization (ESI) in positive ion mode and multiple reactions monitoring (MRM) were used to monitor the ion transitions at m/z 636.4⁺ → 413.3⁺, 594.4⁺ → 494.4⁺, 622.5⁺ → 536.4⁺, respectively. The results indicated that the method had excellent sensitivity and selectivity. The linear range covered from 2 to 500 ng/mL for CT-707and from 1 to 100 ng/mL for M1 and M2. Intra-run and inter-run precisions (in terms of %RSD) were all <15% and the accuracies (in terms of %RE) were within the range of ±15%. The lower limit of quantification (LLOQ), matrix effect, extraction recovery, stability, dilution test and carryover test were also validated and satisfied with the criteria of validation. Finally, the method was successfully applied to a phase I clinical study of ALK-positive advanced NSCLC patients after an oral administration of CT-707.

Kinase inhibitors that target Bcr-Abl are highly effective in the treatment of chronic myeloid leukemia (CML). However, these inhibitors are often invalidated due to the drug resistance. Therefore, the discovery and development of novel Bcr-Abl inhibitors is required to overwhelm the drug resistance in the treatment of CML resistant to the currently used first-line Bcr-Abl inhibitors. Herein we have described a newly developed Bcr-Abl inhibitor CT-721, which displayed potent inhibitory effects on wild-type and T315I mutant Bcr-Abl. It functioned as a typically ATP-competitive inhibitor, superior to other existing Bcr-Abl inhibitors. CT-721 also demonstrated time-dependent inhibition of Bcr-Abl activation and the resultant downstream signaling transduction pathways in Bcr-Abl positive cells. Furthermore, CT-721 induced cell apoptosis and cell cycle arrest, and efficaciously inhibited tumor growth in Bcr-Abl-expressed K562 and KU812 xenograft models in a mechanism-based manner. Further PK/PD studies revealed a positive in vivo correlation between the compound concentration and inhibition of Bcr-Abl activity. Taken together, CT-721 is a potent and time-dependent Bcr-Abl kinase inhibitor, and has shown strong in vitro and in vivo anti-CML activities with a favorable pharmacokinetic profile, differentiating it from other Bcr-Abl kinase inhibitors already approved and current in development for the treatment of CML.