2W0J

Crystal structure of Chk2 in complex with NSC 109555, a specific inhibitor

Summary for 2W0J

• Entry DOI: 10.2210/pdb2w0j/pdb
• Related: 1GXC 2CN5 2CN8
• Descriptor: SERINE/THREONINE-PROTEIN KINASE CHK2, 4,4'-DIACETYLDIPHENYLUREA-BIS(GUANYLHYDRAZONE), NITRATE ION, ... (4 entities in total)
• Functional Keywords: chk2 inhibitor, oncology, kinase, structure-assisted drug design, transferase, nucleotide-binding, li-fraumeni syndrome, serine/threonine-protein kinase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform 2: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 9: Nucleus. Isoform 12: Nucleus. Nucleus, PML body: O96017
• Total number of polymer chains: 1
• Total formula weight: 37032.70

Authors

Lountos, G.T.,Tropea, J.E.,Zhang, D.,Jobson, A.G.,Pommier, Y.,Shoemaker, R.H.,Waugh, D.S. (deposition date: 2008-08-18, release date: 2009-02-10, Last modification date: 2023-12-13)

Primary citation

Lountos, G.T.,Tropea, J.E.,Zhang, D.,Jobson, A.G.,Pommier, Y.,Shoemaker, R.H.,Waugh, D.S.
Crystal Structure of Checkpoint Kinase 2 in Complex with Nsc 109555, a Potent and Selective Inhibitor
Protein Sci., 18:92-, 2009

PubMed Abstract: Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNA-damaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC(50) = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATP-binding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.

PubMed: 19177354
DOI: 10.1002/PRO.16

Experimental method

X-RAY DIFFRACTION (2.05 Å)