Preclinical pharmacokinetics, antitumor activity and single ascending dose tolerability of GBO-006 nanosuspension, a selective polo-like kinase 2 (PLK2) inhibitor

Aim: The present work was executed to develop a biocompatible parenteral formulation for pharmacokinetics, efficacy and toxicology studies of GBO-006, a highly selective polo-like kinase 2 (PLK2) inhibitor that demonstrated significant tumor regression in xenograft models on intraperitoneal alternate day dosing with the DMSO.

Methods: Different technologies such as cosolvency, complexation, and micelle solubilization have been explored but failed to improve the aqueous solubility at higher concentrations. Crystalline and lipid-based nanosuspensions using different surfactants were developed and evaluated for both solubility and stability. Nanosuspensions were prepared by Ultra-Turrax homogenization followed by bead milling and microfluidics evaluated for particle size reduction and morphology. The optimized formulation was checked for pharmacokinetics, antitumor activity, and tolerability.

Conclusions: Nanosuspensions prepared by bead milling were stable for more than 2 weeks and showed reduced particle size of 0.26–0.3 μ. Rat and mouse intravenous and intraperitoneal pharmacokinetic studies showed a significant improvement in Cmax, AUC and systemic clearance of the compound. We have developed a biologically compatible parenteral formulation for a first-in-class, novel anticancer agent that will be progressed toward IND enabling studies.

ID & Participating forAuthor(s) Name: Srinivas Maddi*, Srinivas Lenkalepally, Pratima Srivastava, Duraiswamy A. Jeyaraj, Arnab Roy Chowdhury, Lakshman Rajagopalan, Jang B. Gupta

KEY WORDS: Antitumor activity, Biodistribution, Nanosuspension, Pharmacokinetics, Polo-like kinase 2 inhibitor, Triple negative breast cancer

The development of a novel antitumor agent that is more effective against tumor cells resistant to currently available agents is expected to complement existing treatments in the fight against this deadly disease.[1-3] The polo-like kinases 1 (PLK 1) in cancer is well documented, and PLK3 has been demonstrated to be a tumor suppressor, little is known about the oncogenic significance of PLK2.[4,5] PLK2 kinase activity is essential for centriolar duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells in hypoxic conditions.[6-8] In our attempt to develop ATP-mimetic compounds that are cytotoxic against a panel of cancer cell lines, we identified several sulfonyl pyridopyrimidines that exhibit cytotoxicity at nanomolar concentrations.[9-11] The most potent of these compounds, GBO-006 (2-(1H-indol-5-ylamino)-6-(2, 4-difluorophenylsulfonyl)-8‑methylpyrido [2, 3-d] pyrimidin-7(8H)-one) was found to be a specific PLK2 inhibitor when profiled against a panel of 288 wild-type, 55 mutant and 12 special kinases. The cytotoxic effect of the drug is mediated by apoptosis as evidenced by the induction of Caspase 3/7 activity and by the cleavage of PARP in a dose-dependent manner.[12] Intraperitoneal alternate day dosing of GBO-006 using 100% DMSO as formulation lead to significant tumor regression in Xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. However, GBO-006 showed poor solubility in aqueous media (<0.1 μg/mL), had a low Caco2 permeability (5. 2 × 10−6cm/s) and a crystalline nature, making it very hard to have a feasible formulation with moderate concentration, prompting studies to develop a preclinical formulation. In this paper, we have presented the systematic investigation
on pharmacokinetics and antitumor activity and tolerability of parenteral GBO-006 nanosuspension formulation.


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