Abstract 4537: Pharmacokinetics of PLK2 inhibitor GBO-006-1, developed as a novel first-in-class molecule to treat triple negative breast cancer

Abstract

Abstract Introduction: The goal of this study was to develop a targeted therapy for triple negative breast cancer (TNBC) since these tumors do not respond to hormonal-related therapies or medications that target HER2. TNBC is typically treated with a combination of surgery, radiation, and chemotherapy albeit with worse outcome than patients with breast cancers of other subtypes. We have previously shown that GBO-006-1 (ON 1231320) is a highly selective, ATP competitive PLK2 inhibitor, which induces irreversible mitotic arrest of triple negative breast cancer (TNBC) cell lines and results in their apoptotic death. The goal of our current study was to characterize the drug-like and ADME properties of this molecule, and to optimize the in vivo exposure for preclinical evaluation. Experimental procedures: Drug-like properties were characterized by determining the pH solubility profile, log D, oral absorption potential using PAMPA, metabolic stability using rat and liver microsomes, plasma protein binding, and the inhibitory effect on various CYP isozymes. GBO-006-1 has weakly ionizable groups and did not show any improvement of solubility at various pH values. To overcome this limitation, we developed a co-solvent-based formulation that increased the solubility of the compound. A preclinical formulation was subsequently developed that allowed us to perform PK studies in mice, rats (IV, PO & IP) and dogs (IV) and to conduct efficacy studies with GBO-006-1 as a single agent (10, 30 and 75 mg/kg) and in combination using nude mouse xenograft models. In vitro safety pharmacology was assessed by performing hERG (patch clamp), and genotoxic potential was evaluated using the Ames test. Summary: The solubility of GBO-006-1 was enhanced using a co-solvent approach, which permitted the determination of ADME properties. The solution formulation provided good exposure and bioavailability upon IP administration (41% bioavailability at 3mg/Kg) and dose dependency up to 100 mg/kg. The compound showed moderate to high in vivo clearance in rat and mouse, respectively, and has high plasma protein binding and volume of distribution, with no CYP or hERG inhibition. Exploratory non-GLP toxicity studies are currently ongoing in three species, along with other safety pharmacological studies and ex vivo surrogate biomarker analysis. Conclusion: We were successful in developing a formulation forGBO-006-1, which allowed for parenteral administration. GBO-006-1 showed linear dose escalation in mice that translated into marked efficacy in a triple negative breast cancer xenograft model. Initial safety profiling suggested no hERG inhibition. IND directed studies are currently being conducted to facilitate Phase 1 clinical trials in the near future. Citation Format: ARNAB ROYCHOWDHURY, ATHISAYAMANI JEYARAJ DURAISWAMY, SRINIVASARAO MADDI, CHANDRA DEB, SAYAN MITRA, RAMANA REDDY, MANOJ MANIAR, SHASHIDHAR JATIANI, STEPHEN C. COSENZA, AMOL PADGAONKAR, PREMKUMAR REDDY. Pharmacokinetics of PLK2 inhibitor GBO-006-1, developed as a novel first-in-class molecule to treat triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4537. doi:10.1158/1538-7445.AM2014-4537