Description

Lead Optimisation

The cell cycle checkpoint kinase Chk2 is a central multifunctional player in the induction of cell cycle arrest, DNA repair and apoptosis. The current understanding of Chk2 function in tumour cells, in both a biological and genetic context, suggests that inhibition of the kinase may be able to both sensitise tumour cells to certain damaging agents, whilst also protecting normal cells from damage, thus widening the therapeutic window. It has been demonstrated that disruption of homologous recombination (HR) DNA repair pathways by Chk2 siRNA induces profound cellular sensitivity to the inhibition of poly (ADP-ribose) polymerase (PARP) activity. In addition, transgenic mouse studies have demonstrated that Chk2 abrogation gives rise to protection from radiation.

In vivo studies

Preliminary PK/PD studies have been carried out and demonstrate that compounds from the lead series are well tolerated in mice, and some have good oral availability. Furthermore, the compounds demonstrate significant inhibition of Chk2 activity induced by a DNA damaging agent in a tumour xenograft model. PD studies of CCT241533 in combination with PARP inhibitors are ongoing.

Download the PDF of Chk2 Inhibitor Programme

For more information please contact

Dr Laura Fletcher

+44 (0) 20 3469 6300 .(JavaScript must be enabled to view this email address)