Related Experiment Video
Updated: Jun 9, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program
Hernan Carol1, Christopher L Morton, Richard Gorlick
1Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
Background:
GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP).
Procedures:
GSK690693 was tested in vitro at concentrations from 1 nM to 10 µM, and against the in vivo panel of xenografts at a dose of 30 mg/kg daily × 5 for 6 consecutive weeks. Three measures of in vivo antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event measure based on the median event-free survival (EFS) of treated and control animals for each xenograft.
Results:
GSK690693 inhibited cell growth in vitro with IC(50) values between 6.5 nM and >10 µM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity.
Conclusions:
GSK690693 demonstrated broad activity in vitro, however our results against both the solid tumor and ALL PPTP in vivo panels demonstrate that, as single agent at the dose and schedule used, GSK690693 has only modest antitumor activity.
Insights
GSK690693, an Akt inhibitor, showed broad in vitro activity but modest in vivo antitumor effects in pediatric cancer models. Further research is needed to optimize its therapeutic potential.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- GSK690693 is a novel small molecule inhibitor targeting the Akt kinase, a key regulator of cell survival.
- The Akt pathway influences numerous downstream targets, including those involved in cell growth, apoptosis, and protein synthesis.
Purpose of the Study:
- To evaluate the preclinical efficacy of GSK690693 in pediatric cancer models.
- To assess the in vitro and in vivo antitumor activity of GSK690693.
Main Methods:
- In vitro testing involved concentrations ranging from 1 nM to 10 µM.
- In vivo studies utilized a xenograft model at a dose of 30 mg/kg daily for 6 weeks.
- Antitumor activity was measured by objective response, tumor volume (T/C), and event-free survival (EFS).
Main Results:
- GSK690693 demonstrated in vitro growth inhibition with IC50 values between 6.5 nM and >10 µM.
- In vivo, GSK690693 significantly improved EFS in 32% of solid tumor xenografts, particularly osteosarcomas.
- No objective responses were observed, and only limited intermediate activity was noted in solid tumors.
Conclusions:
- GSK690693 exhibits broad in vitro activity against pediatric cancer cell lines.
- As a single agent at the tested dose and schedule, GSK690693 shows modest in vivo antitumor activity in preclinical pediatric models.
- The study highlights the need for further investigation into optimizing GSK690693's therapeutic application.
Related Concept Videos
01:28Preclinical Development: Overview
01:11Clinical Trials: Overview
01:16Clinical Trials
There are four phases in a clinical trial. A phase one...
01:24Pharmacokinetics in Pediatric Patients: Drug Metabolism