SYST-12 LP-184, A NOVEL ACYLFULVENE-DERIVED TUMOR SITE ACTIVATED SMALL MOLECULE INHIBITS ADULT AND PEDIATRIC CNS TUMOR CELL GROWTH

Abstract Blood-brain barrier (BBB) permeable agents effective against recurrent, chemotherapy-resistant central nervous system (CNS) tumors are urgently needed, particularly in Glioblastoma multiforme (GBM) and atypical teratoid/rhabdoid (ATRT). These represent extremely aggressive lethal types of CNS malignancies. LP-184 is a next-generation acylfulvene class drug candidate has received FDA orphan designations for the treatment malignant gliomas ATRT. creates covalent DNA adducts that selectively repaired via nucleotide excision repair (NER). Repair LP-184-induced damage mediated by ERCC complexes. Consistent with this, we observed 3-6X decreased cancer cell viability U87, M1123 Mayo39 GBM cells treated combination ERCC3 degrader Spironolactone (SP) relative to alone. Mice bearing pre-established subcutaneous U87 xenografts were SP alone, alone or their combination. Tumors recurred after initial regression 5/5 animals whereas showed durable complete without recurrence 4/5 + SP. Thus, likely functions as synthetically agent presence deficiencies. inhibited growth CHLA06 BT37 ATRT lines, IC50s 20-25nM range. induced apoptosis 96 hours these lines measured immunofluorescence cleaved caspase-3 Western blot c-PARP. intravenous at 4 mg/kg twice weekly 2 weeks tumor mice implanted xenografts, 112% inhibition 2/10 being tumor-free study termination. further favorable intracranial bioavailability along vivo BBB permeability comparable other drugs. findings identify promising new support its development treating adult pediatric populations.