Abstract Background and unmet medical need: Among the four major breast cancer metastasis sites (lung, bone, liver, and brain), patients with breast cancer brain metastasis (BCBM) have very limited therapeutic options, poor quality of life, and low overall survival rates. In fact, many clinical trials exclude breast cancer patients with brain metastases due to the limited lifespan of patients after developing brain metastases and unclear penetrance of those agents across the blood-brain barrier (BBB). Current treatment options include whole-brain radiotherapy and chemotherapy which offer limited efficacy and are associated with significant side effects. Major results: We discovered a new generation of antimitotic agents, represented by SB-216 and SP-1-39, that show potent preclinical efficacy against brain and extracranial metastases in BCBM models. Both molecules effectively cross the BBB, inhibit cell growth and migration, and induce apoptosis with low nM potencies. In vivo, SB-216 reduced brain and extracranial metastases in a preventive dosing paradigm, extending overall survival. SB-216 also suppressed the expansion of pre-established brain lesions. In a taxane-refractory TNBC PDX model, SP-1-39 treatments markedly reduced brain and extracranial tumor burden. Conclusion and potential clinical impact: SB-216 and SP-1-39 are promising development candidates to address the high morbidity and mortality associated with TNBC brain metastases, with the potential to contribute meaningfully to the current therapeutic landscape for all molecular subtypes of metastatic breast cancer. In addition, patients diagnosed with other solid tumor types that frequently metastasize to the brain, such as melanoma and lung cancers, or primary brain tumors such as glioma, would also benefit from the availability of a well-tolerated, brain-penetrable new generation of antimitotic agent. Funding Support: NIH/NCI grants R01CA14870 and R01CA276152, the Department of Defense Breast Cancer Research Program BC1900092/BC190092P1 and BC220493. Citation Format: Raisa I. Krutilina, Kelli L. Adeleye, Hilaire Smith, Satyanarayana Pochampally, Souvik Banjeree, Damilola Oluwalana, Mir Shahriar Kamal, Duane D. Miller, Wei Li, Tiffany N. Seagroves. Discovery of Highly Brain Penetrable Antimitotic Agents for the Treatment of Breast Cancer Brain Metastasis abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr P46.
Krutilina et al. (Thu,) studied this question.