Cell Cycle Model

Cell cycle inhibition is critical for the control of many diseases including cancer and inflammation. Although there is a vast academic literature on the mammalian cell cycle, there are no easy ways to predict the effects of therapeutic intervention.

Physiomics' cell cycle model is now allowing detailed investigation of the effects of inhibitors within different parts of the cell cycle. Examples are available of cyclin dependent kinase inhibition, cytotoxic agents like gemcitabine and new agents classes like aurora kinase inhibition.

The quantitative, time-based interconnections of the intricate oscillations and stringent checkpoints of the mammalian cell cycle are poorly understood. Little simulation work has been done to date despite significant academic work simulating the cell cycle in yeast. The model being built by Physiomics is probably the first mammalian cell cycle simulation sufficiently detailed for pharmaceutical development. Such models are also sophisticated, dynamic databases incorporating the latest knowledge from the scientific literature about how key cell control processes work.  

The phases of the cell cycle are shown in the box below.

The Physiomics model represents all stages of the cell cycle with key reactions. The core framework is based on the successive expression of Cyclin D, Cyclin E, Cyclin A and Cyclin B. This allows simulation of many classes of drugs targeting the cell cycle and, in addition, combinations of these drugs. Three examples are shown.

• Cyclin Dependant Kinase inhibitors (G1/S and G2/M phase transition)

The G1/S model component includes representations of:

• the pRb-E2F1,  pRb-E2F3, and P107-E2F4 complex and Cyclin transcription
• the CyclinD-cdk4 and CyclinE-cdk2 roles (other models combine these)
• CyclinA-cdk2 action
• inhibitor action on specific reactions and the influence on the whole cell cycle

For example, many pharmaceutical companies have sought to develop cdk4 inhibitors (involved in the initial stages of the G1 phase) compared to cdk2 inhibitors, crucial in the last part of G1 and in the G1/S transition. The Physiomics model allows this decision to be made with greater accuracy due to well founded cell cycle simulation results.

Some recent validation simulations published by Physiomics in collaboration with Cyclacel in Biosystems Chassagnole et al 2005

• Nucleoside analogs (DNA synthesis)

A detailed DNA synthesis plug-in module has been developed by our partner Bayer Technology Services that can be used to simulate DNA synthesis disruption by nucleoside analogs.

• Aurora Kinase inhibitors (G2/M phase transition)

Physiomics has now started a detailed model of the later parts of the cell cycle. The complex reactions around mitosis have been a fruitful area for pharmaceutical discovery and a source of potent anti-cancer drugs.

Two examples of aurora kinase inhibitor simulation have been presented at the ICSB (Boston, 2005). One showing the effect of VX-680 a Phase II Aurora kinase inhibitor in a single cell model Chassagnole et al. and in SystemCell Finney et al. a multi cellular environment allowing virtual FACS simulations.

For more information on this work please contact us

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