Checkpoint kinase 1 (Chk1) – pre-clinical candidate

Checkpoint kinase 1 (Chk1) – pre-clinical candidate

Chk1 is a critical component of the DNA damage response checkpoint, especially in cancer cells, and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumour activity of DNA damaging chemotherapy drugs.

Structure-guided fragment elaboration was utilized to identify and develop a novel series of Chk1 inhibitors, culminating in the identification of V158411, a potent ATP-competitive inhibitor of Chk1 and Chk2. Read more

X-ray crystal structures of compounds bound to the ATP binding site of Chk1 (PDB code V158411/ Chk1: 5DLS)

V158411 potentiated the anti-tumour activity of irinotecan in a variety of human colon tumour xenograft models, without additional systemic toxicity.

These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents, to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation.

V158411 potentiates irinotecan cytotoxicity in human tumour xenografts. (A) nu/nu mice bearing established colon xenograft tumours were treated once weekly with either vehicle, irinotecan, V158411 or the combination of irinotecan followed by V158411 2 hours later. Tumour size and body weight were measured every 3 days. (B) Summary of in vivo responses to irinotecan plus V158411 combination therapy. Read more

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