Synthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors |
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Authors: | Oza Vibha Ashwell Susan Brassil Patrick Breed Jason Ezhuthachan Jaychandran Deng Chun Grondine Michael Horn Candice Liu DongFang Lyne Paul Newcombe Nicholas Pass Martin Read Jon Su Mei Toader Dorin Yu Dingwei Yu Yan Zabludoff Sonya |
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Affiliation: | AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Vibha.Oza@astrazeneca.com |
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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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