3ZO2

The Synthesis and Evaluation of Diazaspirocyclic Protein Kinase Inhibitors

Summary for 3ZO2

• Entry DOI: 10.2210/pdb3zo2/pdb
• Related: 3ZO1 3ZO3 3ZO4
• Descriptor: CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA, CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA, 6-(2,9-Diazaspiro[5.5]undecan-9-yl)-9H-purine, ... (6 entities in total)
• Functional Keywords: transferase-inhibitor complex, transferase/inhibitor
• Biological source: BOS TAURUS (BOVINE); More
• Total number of polymer chains: 2
• Total formula weight: 43798.69

Authors

Allen, C.E.,Chow, C.L.,Caldwell, J.J.,Westwood, I.M.,van Montfort, R.L.,Collins, I. (deposition date: 2013-02-20, release date: 2013-03-06, Last modification date: 2023-12-20)

Primary citation

Allen, C.E.,Chow, C.L.,Caldwell, J.J.,Westwood, I.M.,van Montfort, R.L.,Collins, I.
Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases.
Bioorg. Med. Chem., 21:5707-5724, 2013

PubMed Abstract: With the success of protein kinase inhibitors as drugs to target cancer, there is a continued need for new kinase inhibitor scaffolds. We have investigated the synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles through ring-closing metathesis were demonstrated. Diazaspirocycles directly linked to heteroaromatic hinge binder groups provided ligand efficient inhibitors of multiple kinases, suitable as starting points for further optimization. The binding modes of representative diazaspirocyclic motifs were confirmed by protein crystallography. Selectivity profiles were influenced by the hinge binder group and the interactions of basic nitrogen atoms in the scaffold with acidic side-chains of residues in the ATP pocket. The introduction of more complex substitution to the diazaspirocycles increased potency and varied the selectivity profiles of these initial hits through engagement of the P-loop and changes to the spirocycle conformation, demonstrating the potential of these core scaffolds for future application to kinase inhibitor discovery.

PubMed: 23920481
DOI: 10.1016/j.bmc.2013.07.021

Experimental method

X-RAY DIFFRACTION (1.98 Å)