Myrtleciclib, a CDK4/6/9 Inhibitor for the Treatment of Aggressive Cancers

Background: Selective Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of breast cancer and have potential in other cancers, being manageable drugs yet with some bone marrow toxicity. Selective CDK9 inhibitors (CDK9i) never advanced into clinical use, partly due to side effects, including gastrointestinal toxicity, and a small window between activity and cytotoxicity, which results in a narrow therapeutic index (TI).

Method: To overcome the drawbacks of CDK4/6 and CDK9 inhibitors, we have developed myrtleciclib, a selective CDK4/6/9 inhibitor with few non-critical molecular off-targets.

Results: Myrtleciclib appears to bind to an allosteric site, unlike all other CDK4/6i and CDK9i acting by an ATP-competitive mechanism, which supports target specificity. Myrtleciclib's anti-proliferative effects are greater and its Therapeutic Index (TI) is broader than CDK9 and CDK4/6-only inhibitors. This can be explained by a moderate target inhibition, resulting in limited cytotoxicity. Moreover, we documented a synergy between CDK9 and CDK4/6 pathways inhibition, justifying increased drug efficacy, yet such synergy can only be achieved when the inhibition of both CDK9 and CDK4/6 is embedded within the same molecule and balanced within a certain ratio, as it is the case with myrtleciclib. Unlike CDK4/6i, myrtleciclib also induces cell death and apoptosis selectively on cancer cell lines, not on bystander cells. Synergy between myrtleciclib and other drugs with complementary Mechanism of Action (MoA) has also been documented.

Conclusion: CDK4/6/9i might represent a new frontier in cancer treatment to overcome the limitations of CDK4/6i and CDK9i for the treatment of cancers, including aggressive cancers with high unmet needs.