Structure vs Induction

Structure/Induction Relationships in CYP1A

The induction of CYP1A occurs primarily via activation of the aryl hydrocarbon receptor (1). The activated receptor moves to the nucleus and activates transcription of the 1A genes, primarily CYP1A1 and CYP1A2 in humans.

Similarly to structure toxicity relationships, there is variation in the ability of a series of compounds to induce CYP1A based on structure. ACTIVTox provides a reproducible, high throughput system to examine these relationships.

Structural variants have different inducing ability

Figure 1 shows a series of indole-containing compounds that have been examined using the ACTIVTox CYP1A induction assay. These compounds are commonly used tyrosine kinase inhibitors. SU5416 and SU4312 are directed against the VEGF receptor (2), GW5074 against Raf kinase (3), IC261 against casein kinase I (4) and indirubin-3-oxime against cyclin-dependent kinase and glycogen synthetase kinase (5).

Figure 1. A series of indole containing kinase inhibitors.

Figure 2 shows that each of these compounds have very different effects on CYP1A induction when assayed at 10µM concentrations. SU5416 and SU4312, in particular, are both directed against the VEGF receptor tyrosine kinase Flt-1. SU5416 is the most potent CYP1A inducer, while SU4312 is the least potent.

Figure 2. Induction of CYP1A by a series of
indole containing kinase inhibitors.

ACTIVTox has the ability to identify potential toxic liabilities early in the drug discovery process, before entering clinical trials.

References

1. Ma, Q, Lu, AY (2007) CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies. Drug Metab. Disp. 35, 1009 – 1016.
2. Mendel, DB, et al. (2000) The Angiogenesis Inhibitor SU5416 Has Long-lasting Effects on Vascular Endothelial Growth Factor Receptor Phosphorylation and Function. Clin. Can. Res. 6, 4848 – 4858.
3. Schultheiss, C, et al. (2006) In vivo characterization of endothelial cell activation in a transgenic mouse model of Alzheimer's disease. Angiogenesis 9, 59 – 65.
4. Chin, PC, D’Mello, SR (2005) Brain chemotherapy from the bench to the clinic: targeting neuronal survival with small molecule inhibitors of apoptosis. Front. Biosci. 10, 552 – 568.
5. Behrend, L. et al. (2000) IC261, a specific inhibitor of the protein kinases casein kinase 1–delta and –epsilon, triggers the mitotic checkpoint and induces p53–dependent postmitotic effects. Oncogene 19, 5303 – 5313.
6. Meijer, L et al. (2003) GSK–3–selective inhibitors derived from Tyrian purple indirubins. Chem. Biol. 10, 1255 – 1266.