Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 (PLK2) inhibitor for the treatment of triple negative breast cancer

Authors

  • Srinivas Maddi
  • Ravi Akkireddy
  • Srinivas Lenkalapelly
  • Pratima Srivastava
  • Joshodeep Boruwa
  • Chandra Deb
  • Arnab Roy Chowdhury
  • Duraiswamy A. Jeyaraj
  • Ramana Reddy
  • Premkumar Reddy
  • Manoj Maniar
  • Sachin Bansal
  • Jang B. Gupta

DOI:

https://doi.org/10.5599/admet.4.4.341

Keywords:

PLK2 inhibitor, Pharmacokinetics, Efficacy, Triple negative breast cancer

Abstract

GBO-006 was shown to be a highly specific and selective PLK2 inhibitor that promoted mitotic arrest in various cancer cell lines, subsequently resulting in their apoptotic death.  Intraperitoneal alternate day dosing of GBO-006 using 100 % DMSO as formulation showed significant tumor regression in xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. These studies necessitated the development of a suitable and GRAS (generally considered as safe) preformulation for pharmacokinetic and efficacy studies. GBO-006 possesses challenging physicochemical and biopharmaceutical properties like poor solubility in aqueous media, low permeability and a crystalline nature. Different methods like cosolvency, complexation and micellar solubilization were employed to improve the solubility of GBO-006.  A strategy of co-solvency is used to solubilize the GBO-006 up to 10 mg/mL. A formulation with 20 % DMSO, 40 % PEG 400, 30 % of 100 mM citrate buffer (pH 3.0) and 10 % solutol displayed clear solution without any visual precipitation of the drug even after 2 weeks of storage. GBO-006 showed moderate clearance in rat and high systemic clearance in mouse and dog. It showed poor oral bioavailability across all species. Intraperitoneal dosing of GBO-006 demonstrated the linear exposure. GBO-006 showed significant inhibition of tumor progression.  

 

 

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Published

26-12-2016

How to Cite

Maddi, S., Akkireddy, R., Lenkalapelly, S., Srivastava, P., Boruwa, J., Deb, C., Chowdhury, A. R., Jeyaraj, D. A., Reddy, R., Reddy, P., Maniar, M., Bansal, S., & Gupta, J. B. (2016). Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 (PLK2) inhibitor for the treatment of triple negative breast cancer. ADMET and DMPK, 4(4), 314–326. https://doi.org/10.5599/admet.4.4.341

Issue

Section

Original Scientific Articles