Full characterization of a third-generation Bcr-Abl inhibitor to cure CML
Chronic Myeloid Leukemia (CML) is one of the most prevalent and difficult blood and bone marrow cancers to cure. This type of leukemia, often categorized as chronic, may suddenly evolve from slow progression into a rapidly growing and aggressive cancer, then propagate throughout the body and disseminate into multiple organs. The kinase Bcr-Abl plays a key role in CML propagation.
Treatments exist to cure CML. However, first-generation kinase inhibitors, such as Imatinib (GLEEVEC®), show a lack of efficacy over time due to the emergence of resistance associated with the T315I Abl mutation. More potent second-generation Bcr-Abl inhibitors have been developed, demonstrating higher efficacy in inhibiting Bcr-Abl, but they also showed limited effects on the T3151 mutation.
Based on computational modeling and the structure–activity relationship (SAR), Yinghui Sun synthesized a new chemical structure – CT-721 – and fully characterized its action on Bcr-Abl. This compound is an ATP-competitive inhibitor and displays high potency on both Bcr-Abl wild types and mutants, including T315I. Inhibition of signaling downstream Bcr-Abl pathways, induced apoptosis, and anti-proliferative effects were fully documented in cancer cell line expressing the enzyme, including K562 and KU812, but not in other cancer cell lines lacking it.
Mice Xenograft models were used to assess the in vivo potency of CT-721. Interestingly, the compound displays compelling pharmacodynamic properties (PK/PD), making it a good candidate for further studies at the clinical stage.
With CT-721, the race for third-generation CML ATP-competitive inhibitors has begun. Now is the perfect time for you get into the game.
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.
Journal of Cancer, 2017; 8(14): 2774–2784.