Title : Preclinical development of GMC1, a novel molecule targeting FKBP52 for the treatment of castration resistance prostate cancer
Abstract:
Purpose: GMC1 directly inhibits FKBP52, effectively blocking androgen receptor dependent gene expression and androgenstimulated proliferation. This makes it an attractive option for the treatment of hormone-dependent and hormone-independent prostate cancer. This study investigated an analytical method for GMC1 quantification, pre-formulation characteristics of GMC1, and developed intravenous formulations for the evaluation of GMC1 in animal models.
Method: An LC/MS/MS method for the quantification of GMC1 in solution, plasma and urine was developed, validated and applied to the determination of the stability, log P, plasma protein binding and solubility of GMC1 in various solvents. Liposomal formulations and co-solvent systems with various ratios of high capacity vehicles were formulated and the optimal formulation applied, at 2 mg/kg single IV bolus dose, to the pharmacokinetic study of GMC1 in a rat model. In vivo efficacy study has been performed on xenograft mouse model
Result: The intra- and inter-day accuracy (%RE) and precision (%CV) of the LC/MS/MS method ranged from 1.6 – 11.7 % and 1.4 – 8.8 %, respectively. GMC1 is stable in solid and solution state, moderately lipophilic (log P = 1.38 ± 0.05), poorly water soluble (0.4 ± 0.01 mg/mL), and highly plasma protein bound (>71%). The optimal formulation consisting of PEG 300 and Labrasol ® (1:1, v/v) allowed us to achieve a GMC1 concentration of 10mg/mL, and tolerated an aqueous environment. GMC1 has a tri-exponential disposition with a Cmax of 7.6 ± 1.97 mg/L, clearance of 0.53 L/kg/hr, α-distribution, β-phase and terminal elimination half-lives of 0.1 ± 0.04 hr, 1.2 ± 0.34 hr, and 19.7 ± 5.09 hr respectively. The in vivo efficacy study in nude mice with LNCaP-ID4 xenograft showed significant tumor inhibition in the GMC1 treated group compared with the control group.
Conclusion: The LC/MS/MS method, formulations, pharmacokinetics and efficacy study can be applied to the clinical development of GMC1.
Takeaway Notes:
•This project shows a well-designed preclinical development of a novel first-in-class drug for castration resistant prostate cancer, a deadly disease.
•Other faculty could use this project as an example to design their research or teach the student the essential components for a preclinical study.
•It can provide a practical solution to help a designer on solving seminar formulation study of other drugs.
•It can provide new information to assist in design a preclinical study for other drugs.
