Targeting CDK4: The Therapeutic Potential of AU2-94 in Combating Cancer

Cyclin-dependent kinases play a crucial role in cellular development, and specific CDK4/6 inhibitors have been shown to extend the lifespan of certain breast cancer patients. However, these drugs have limitations due to off-target effects, leading to reduced dosages and treatment interruptions, which can build resistance and compromise their efficacy. A new compound, AU2-94, has been identified as a highly selective CDK4 inhibitor with potential for treating various CDK4-dependent cancers, including different types of breast cancer, colorectal cancer, and glioblastoma.

AU2-94 demonstrates a high level of specificity for CDK4 with a Ki of 2 nM, significantly lower than that for CDK6 at 279 nM. It effectively halts the cell cycle in the G1 phase and curbs the proliferation of cancer cells. Notably, AU2-94 also reduces the levels of CDK2, Cyclin E2, Cyclin A2, and Cyclin B1, and triggers apoptosis by lowering Bcl-2 and FOXM1 levels. In contrast to its impact on cancer cells, it has minimal effects on the cell cycle, senescence, or apoptosis in human bone marrow cells, and unlike existing CDK4/6 inhibitors, it does not reduce the counts of lymphocytes and neutrophils.

In in vivo tumor models, AU2-94 has shown high efficacy, causing tumor regression in ER+ breast cancer xenografts and an 86% tumor-free rate in a specific model of luminal breast cancer. In colorectal cancer xenografts, it significantly inhibited tumor growth in a dose-dependent manner without overt toxicity. Pharmacokinetic and pharmacodynamic studies indicate a 500-fold higher concentration of AU2-94 in tumors compared to plasma, highlighting its tumor-targeting specificity. Several robust biomarkers and pharmacodynamic markers were identified, and AU2-94 has shown promise in crossing the blood-brain barrier, reducing tumor burden, and improving survival in glioblastoma models.

Furthermore, AU2-94 has been found to enhance the anti-cancer effects of PI3K/Akt/mTOR and HER2 inhibitors when used in combination. It is a CDK4 inhibitor with high selectivity against a panel of 360 human kinases, which may contribute to its better safety profile compared to existing CDK4/6 inhibitors. With its high oral bioavailability, potent antitumor activity, and favorable safety profile, AU2-94 is a promising candidate for clinical development.