WF-229A

WF-229A is a novel, blood-brain barrier (BBB)-permeable small molecule inhibitor of truncated glioma-associated oncogene homolog 1 (tGLI1). It is specifically designed to address glioblastoma (GBM) by overcoming resistance to CDK4/6 inhibitors, a process often mediated by tGLI1-driven transcription. WF-229A was developed as a safer alternative to ketoconazole, which inhibits tGLI1 but causes significant toxicity due to potent CYP3A4 inhibition. Preclinical studies indicate that WF-229A lacks significant CYP3A4 inhibition and demonstrates a high maximal tolerated dose (MTD) in vivo. In combination with CDK4/6 inhibitors, it has shown synergistic effects in inducing apoptosis and reducing the stemness and invasiveness of GBM cells.