Advancements in Targeted Therapy: The Development and Pharmacokinetics of GBO-006-1 for Triple Negative Breast Cancer

The aim of this research was to formulate a novel treatment for triple negative breast cancer (TNBC), which is resistant to traditional hormone and HER2 therapies. Surgery, radiation, and chemotherapy are the usual treatments, but they yield poorer outcomes compared to other breast cancer types. Our previous research identified GBO-006-1 (ON 1231320) as a selective and potent PLK2 inhibitor that halts TNBC cell division and triggers cell death. This study aimed to investigate the drug characteristics and absorption, metabolism, excretion, and toxicity (ADME) profile of GBO-006-1 to prepare it for preclinical testing.

We assessed the solubility, absorption, metabolic stability, protein binding, and effects on various enzymes of GBO-006-1. The compound's solubility was limited due to its weakly ionizable nature, so we formulated a co-solvent to enhance it. This formulation enabled pharmacokinetic studies in mice, rats, and dogs, and efficacy tests using nude mouse xenografts. Safety was evaluated through hERG and Ames tests.

The co-solvent formulation of GBO-006-1 improved its solubility, allowing for ADME analysis. It showed good bioavailability and dose-dependent exposure up to 100 mg/kg after intraperitoneal administration. The compound demonstrated moderate to high clearance rates and high plasma protein binding without inhibiting CYP or hERG. Preliminary non-GLP toxicity and safety pharmacology studies are underway.

The formulation development for GBO-006-1 enabled its intravenous administration, and it showed significant efficacy in a TNBC xenograft model. Initial safety assessments indicated no hERG inhibition. We are currently conducting IND-directed studies to prepare for Phase 1 clinical trials.