Advancements in CDK4/6 Inhibition: The Emergence of FCN-437 for Solid Tumor Therapy

The abstract discusses the development of a new CDK4/6 inhibitor named FCN-437, designed to address limitations in treating solid tumors, especially those that have metastasized to the brain. CDK4 and CDK6, when complexed with D-type cyclins, phosphorylate the Retinoblastoma protein (Rb), which is crucial for the cell cycle's transition from G1 to S phase. Disruptions in this signaling pathway are prevalent in cancer. While first-generation CDK inhibitors have shown toxicity and limited efficacy, the second generation, including ribociclib, palbociclib, and abemaciclib, has demonstrated improved progression-free survival for ER+/HER2- breast cancer. However, their effectiveness is hindered by poor blood-brain barrier penetration.

FCN-437 is presented as a selective and orally bioavailable CDK4/6 inhibitor with broad-spectrum anti-proliferating effects on Rb+ tumor cells from various solid tumors. It shows superior potency to ribociclib and comparable efficacy to palbociclib. In tumor xenograft models, FCN-437 significantly inhibited tumor growth, either matching or surpassing the approved inhibitors. The compound also synergizes well with letrozole or fulvestrant and exhibits favorable pharmacokinetics, including improved bioavailability and preferential distribution to brain tissues in rats, suggesting enhanced blood-brain barrier permeability.

Non-clinical studies indicate that FCN-437 has a favorable safety profile, with low hERG activity, no cardiotoxicity, and no CYP450 induction or inhibition, reducing the risk of drug interactions. Overall, FCN-437 is highlighted for its drug-like properties, enhanced efficacy, improved pharmacokinetics with BBB penetration, and preferable safety profiles. It is considered a promising candidate for targeted therapy for advanced solid tumors with brain metastases, either as a single agent or in combination. A phase 1 clinical trial for FCN-437 was approved by the NMPA in 2018.