Structure-based design of Aurora A & B inhibitors.
The Aurora family of serine/threonine kinases are mitotic regulators involved in centrosome duplication, formation of the bipolar mitotic spindle and the alignment of the chromosomes along the spindle. These proteins are frequently overexpressed in tumor cells as compared to normal cells and are therefore potential therapeutic oncology targets. An Aurora A high throughput screen revealed a promising sub-micromolar indazole-benzimidazole lead. Modification of the benzimidazole portion of the lead to a C2 linker with a phenyl ring was proposed to achieve novelty. Docking revealed that a conjugated linker was optimal and the resulting compounds were equipotent with the lead. Further structure-guided optimization of substituents on the 5 & 6 position of the indazole led to single digit nanomolar potency. The homology between the Aurora A & Aurora B kinase domains is 71% but their binding sites only differ at residues 212 & 217 (Aurora A numbering). However interactions with only the latter residue may be used for obtaining selectivity. An analysis of published Aurora A and Aurora B X-ray structures reveals subtle differences in the shape of the binding sites. This was exploited by introduction of appropriately sized substituents in the 4 & 6 position of the indazole leading to Aurora B selective inhibitors. Finally we calculate the conformational energy penalty of the putative bioactive conformation of our inhibitors and show that this property correlates well with the Aurora A binding affinity.
S*BIO Pte Ltd., 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, 117 528, Singapore, Singapore. anders_poulsen@sbio.com
Anders
A
Poulsen
Anthony
A
William
Angeline
A
Lee
Stéphanie
S
Blanchard
Eeling
E
Teo
Weiping
W
Deng
Noah
N
Tu
Evelyn
E
Tan
Eric
E
Sun
Kay Lin
KL
Goh
Wai Chung
WC
Ong
Chee Pang
CP
Ng
Kee Chuan
KC
Goh
Zahid
Z
Bonday
D064127:Aurora Kinases; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases