CDK4-selective inhibitor AU2-94 for the treatment of advanced and therapy-resistant prostate cancer

Biochemical and molecular analyses were performed to define CDK4 selectivity, RB pathway engagement, transcriptional consequences, and downstream effects on cell cycle and resistance-associated programs. AU2-94 was also tested in combination with standard-of-care therapies (enzalutamide, docetaxel) and the PI3K inhibitor alpelisib. RESULTS: AU2-94 exhibited greater selectivity for CDK4 compared to atirmociclib.

AU2-94 supressed proliferation across prostate cancer models irrespective of AR status and retained activity in aggressive and therapy-resistant settings. In RB-proficient models, AU2-94 reduced RB phosphorylation, attenuated E2F1-dependent transcriptional outputs, activated AR signalling, and decreased expression of proliferation-associated factors such as c-Myc and FOXM1. In vivo, AU2-94 significantly inhibited tumour growth in both AR-driven (LNCaP) and AR-independent (PC3) xenografts and suppressed RB pathway signalling in tumour tissue.

Moreover, AU2-94 enhanced anti-tumour responses in combination with enzalutamide, docetaxel, or alpelisib, demonstrating additive or synergistic effects associated with reinforced cell-cycle blockade and suppression of resistance-associated signalling. CONCLUSION: These findings establish selective CDK4 inhibition as a therapeutically active and mechanistically rational strategy in prostate cancer, and support AU2-94 as a candidate for further preclinical and clinical development, including in combination regimens for advanced and therapy-resistant disease.