ServicesTarget Validation

Case study: validate targets of the Bcl2 family

A model of the intrinsic pathways of apoptosis has been created through a collaboration with ValiRx plc to aid in their research and development of novel therapeutics targeting the bcl2 family of proteins.

We have created a large model of DNA damage-induced apoptosis and calibrated it for the prostate cancer cell line, LNCaP. The model includes over 120 reactions, over 80 species, more than 200 parameters and has been created with information carefully curated from the available scientific literature.

Our mechanistic simulations can simulate the effect of inhibition of different targets. The figure shows the effect of altering the expression of bcl-xL on LNCaP viability after treatment with mitoxantrone. The simulations agree with experimental results (figure 1) and helped our client to validate bcl-xL as a drug target.

Target validation
Fig. 1 Altering the expression of potential drug target bcl-xL greatly impacts the effect of
mitoxantrone-induced cell death. Hardy, A. et al, Abstract No I07, ICSB Annual Meeting 2007,
Long Beach, CA. Experimental data from Lebedeva I et al., Cancer Res (2000) 60:6052-6060.
 

Our model was used to perform predictions for optimal targets of the Bcl2 family alone and in combination. The resulting simulations and conclusions were decisive in supporting both “go” and “no-go” decisions for potential drug targets.