2YER

Synthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors

Summary for 2YER

• Entry DOI: 10.2210/pdb2yer/pdb
• Related: 1IA8 1NVQ 1NVR 1NVS 1ZLT 1ZYS 2AYP 2BR1 2BRB 2BRG 2BRH 2BRM 2BRN 2BRO 2C3J 2C3K 2C3L 2CGU 2CGV 2CGW 2CGX 2WMQ 2WMR 2WMS 2WMT 2WMU 2WMV 2WMW 2WMX 2X8D 2X8E 2X8I 2XEY 2XEZ 2XF0 2YDI 2YDJ 2YDK 2YEX 2YM3 2YM4 2YM5 2YM6 2YM7 2YM8
• Descriptor: SERINE/THREONINE-PROTEIN KINASE CHK1, 5-(HYDROXYMETHYL)-8-(1H-PYRROL-2-YL)-2H-[1,2,4]TRIAZOLO[4,3-A]QUINOLIN-1-ONE, SULFATE ION, ... (5 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: O14757
• Total number of polymer chains: 1
• Total formula weight: 32589.49

Authors

Read, J.A.,Breed, J.,Haye, H.,McCall, E.,Vallentine, A.,White, A.,Otterbein, L. (deposition date: 2011-03-30, release date: 2012-03-14, Last modification date: 2024-05-08)

Primary citation

Oza, V.,Ashwell, S.,Brassil, P.,Breed, J.,Ezhuthachan, J.,Deng, C.,Grondine, M.,Horn, C.,Liu, D.,Lyne, P.,Newcombe, N.,Pass, M.,Read, J.,Su, M.,Toader, D.,Yu, D.,Yu, Y.,Zabludoff, S.
Synthesis and Evaluation of Triazolones as Checkpoint Kinase 1 Inhibitors.
Bioorg.Med.Chem.Lett., 22:2330-, 2012

PubMed 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.

PubMed: 22342147
DOI: 10.1016/J.BMCL.2012.01.043

Experimental method

X-RAY DIFFRACTION (1.83 Å)