Dipyridamole analogs uncouple two dipyridamole activities: induction of cancer cell death and inhibition of platelet aggregation

Statins, well-known for their cholesterol-lowering effects, have shown promise in inducing tumor-specific cell death by disrupting the mevalonate (MVA) pathway, a metabolic route critical for cancer cell proliferation and survival. However, their anticancer efficacy is hampered by a compensatory feedback mechanism involving the sterol regulatory element-binding protein 2 (SREBP2). When statins deplete cellular cholesterol, SREBP2 activation induces expression of genes involved in the MVA pathway, which counteract the anti-tumor effects of statin treatment. Our previous work revealed dipyridamole (DP), an established antiplatelet agent, as an enhancer of statins’ anticancer effects by inhibiting the SREBP-induced feedback response. Despite this advance, the broad pharmacological profile and antiplatelet activity of DP limit its applicability in the treatment of cancer patients. To address this limitation, we employed high-content image analysis to screen a library of 44 DP analogs for their ability to potentiate statin-induced pro-apoptotic activity in prostate and breast cancer cell lines. Concurrently, we evaluated these analogs for their impact on platelet aggregation. Remarkably, we identified five DP analogs that exhibited enhanced efficacy as potentiators of statin-induced apoptosis compared to DP, with undetectable antiplatelet aggregation activity. These data show these two DP activities can be successfully uncoupled using a medicinal chemistry strategy. This uncoupling is essential for reducing potential adverse effects on blood coagulation, particularly in cancer patients who are often at higher risk for bleeding compared with patients without cancer or patients undergoing surgery. This study not only demonstrates the feasibility of selectively enhancing statin efficacy through DP analogs but also paves the way for developing novel chemical entities that target SREBP in cancer, offering a promising strategy for safer, more targeted cancer therapies. This research contributes to advancing the understanding of MVA pathway modulation as a therapeutic strategy for cancer treatment.