Abstract 321: BTE-EN1, a novel acting heterobifunctional compound inhibiting bone destruction by established prostate cancer bone metastasis

Bone destruction by prostate cancer (PCa) metastasis is a major cause of morbidity and mortality. In order to destroy bone, PCa and bone cells stimulate each other in a process that requires their coordinated movement within bone itself. To therapeutically inhibit this process, we synthesized the first-in-class heterobifunctional compound, BTE-EN1. One group is a selective inhibitor of cancer cell motility, discovered by us (Nature Communications 2018). It is chemically coupled to a bisphosphonate group, which binds to bone mineral and enables targeted delivery of the therapeutic to bone-destructive lesions. We sought to test whether BTE-EN1 would be active against well-established bone-destructive PCa metastasis and to evaluate its potential as a therapeutic. We used the state-of-the-art caudal artery injection model to selectively deposit human PCa cells into the long bones of the leg in mice and let them grow for two weeks, thus emulating the scenario of established disease in patients. We then began weekly administration of BTE-EN1 for six weeks, quantified bone destruction by CT imaging and demonstrated a significant decrease in bone destruction by 62%, compared to control. In a separate study, BTE-EN1 treatment prior to intra-cardiac injection of PCa cells led to dose-dependent significant prolongation of life, a finding not seen with bisphosphonate and denosumab therapies. Comprehensive in vitro studies demonstrate that BTE-EN1 retains the cellular and molecular pharmacologic and pharmacodynamic properties of its two functional groups. BTE-EN1 exhibited no toxicity when mice were treated at a dose 4000-fold higher than that showing efficacy and lacked toxicity in the NCI-60 cell line panel screen. Additional studies supporting translation to the clinic include non-interference with therapy used to treat advanced PCa, as well as inhibition of cell motility across a panel of human cancer cell types associated with bone destruction. In conclusion, BTE-EN1 is a first-in-class highly active heterobifunctional compound that inhibits bone destruction in established PCa bone metastasis and is well tolerated. Our data strongly suggests that BTE-EN1 has high potential for translation into humans and constitutes a novel therapeutic strategy. Citation Format: Fangfang Qiao, Ryan Gordon, Abhinandan Pattanayak, Katelyn O’Neill, Weining Chen, Prathap R. Mukthapuram, Amar Natarajan, Raymond Bergan. BTE-EN1, a novel acting heterobifunctional compound inhibiting bone destruction by established prostate cancer bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 321.