DDDR-30. UNRAVELING THE NOVEL ANTI-TUMOR MECHANISM OF ST-401, A BRAIN PENETRANT MICROTUBULE TARGETING AGENT

Abstract Microtubule targeting agents (MTAs) are indispensable medicines to treat a wide range of cancers. While evidence suggests that glioblastoma (GBM) is sensitive disruptions in microtubule (MT) functions; most MTAs do not reach the brain. To address this limitation, we developed brain-penetrant MTA, ST-401, kills patient-derived GBM culture at nanomolar concentrations, binds colchicine sites through unique interaction mode, gently and reversibly inhibits MT assembly cancer cells novel anti-tumor mechanism as determined by analysis its activity NCI 60 cell panel compared Approved Oncology Agents library (Horne et al. (2020) Neuro-Onc Adv. 3(1): vdaa165).We used flow cytometry confirm nocodazole (10-100 nM) treatment HCT116 triggered apoptosis, necrosis, accumulation autophagosomes, well increase p-P53. By sharp contrast, ST-401 did trigger these responses. Live imaging showed NOC preferentially mitosis whereas interphase. ScRNAseq HCT-116 down-regulates MYC mRNA expression, suggesting might affect function. protein levels regulated multiple mechanisms, including phosphorylation residue Thr58 promotes ubiquitination proteasome degradation. We discovered increases on expression both line, U251.Our result involve death interphase reduced expression. Funded NIH (CA244213 NS NS106924 NS).