AI Article Synopsis
- Checkpoint kinase 1 (Chk1) is crucial for the cell's response to DNA damage, and this study focuses on developing inhibitors of Chk1 based on triazoloquinolones/triazolones (TZs).
- The research led to the discovery of effective Chk1 inhibitors (14c, 14h, and 16e) and highlighted the challenge of enhancing their physicochemical and pharmacokinetic properties for testing.
- In a hollow fiber pharmacodynamic model, the inhibitor 16e was shown to effectively reduce cell cycle arrest caused by the chemotherapy drug topotecan, supporting the potential use of TZs in combination with chemotherapeutic treatments and radiotherapy.
Article Abstract
Checkpoint kinase 1 (Chk1, CHEK1) is a Ser/Thr protein kinase that plays a key role in mediating the cellular response to DNA-damage. Synthesis and evaluation of a previously described class of Chk1 inhibitors, triazoloquinolones/triazolones (TZs) is further described herein. Our investigation of structure-activity relationships led to the identification of potent inhibitors 14c, 14h and 16e. Key challenges included modulation of physicochemical properties and pharmacokinetic (PK) parameters to enable compound testing in a Chk1 specific hollow fiber pharmacodynamic model. In this model, 16e was shown to abrogate topotecan-induced cell cycle arrest in a dose dependent manner. The demonstrated activity of TZs in this model in combination with a chemotherapeutic agent as well as radiotherapy validates this series of Chk1 inhibitors. X-ray crystal structures (PDB code: 2YEX and 2YER) for an initial lead and an optimized analog are also presented.
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| http://dx.doi.org/10.1016/j.bmcl.2012.01.043 | DOI Listing |
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