Karthigeyan et al.
kinase. Further, by means of SERS technique, we could
establish the surface binding of this scaffold with the Aur-
ora family kinases in general. Moreover, this binding
could effectively inhibit the kinase activity of both
enzymes in vitro. Similarly, the inhibition was also con-
vincingly established in cell lines upon measuring the
ploidy status and the histone H3 S10 phosphorylation
level after treatment with PTK66. Thus, the novel resorci-
nol scaffold containing PTK66 is proven to target the
Aurora family kinases. Future research may be directed
to design more potent and specific inhibitors of Aurora
kinases. Most of the reported inhibitors possess adenine-
like scaffolds with two 5 or 6 member rings that make
contact with the hinge region through residues such as
Leu210, Glu211, Tyr212, Ala213, Leu139, Val147 and
Leu263 (17). Similarly, the resorcinol scaffold has been
shown for the first time to contact some of these key
residues from the outer surface rather than the ATP
pocket. This binding may be one of the reasons for the
low micromolar inhibition of Aurora A kinase by PTK66,
which can be tailored to increase the potency by suitable
modification of this scaffold in future. Importantly, the
same scaffold can be targeted to a similar surface pocket
over Aurora B kinase, which can effectively hydrogen
bond with Ala157, a key residue that is often targeted by
Aurora B kinase inhibitor molecules (18). This finding
could be considered as noteworthy information to the
future design of potent dual inhibitors of Aurora kinases
using this resorcinol scaffold.
2. Kelly K.R., Ecsedy J., Mahalingam D., Nawrocki S.T.,
Padmanabhan S., Giles F.J., Carew J.S. (2011) Target-
ing aurora kinases in cancer treatment. Curr Drug Tar-
gets;12:2067–2078.
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Coumar M.S. (2011-2013) Aurora kinase inhibitor
patents and agents in clinical testing: an update.
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4. Pollard J.R., Mortimore M. (2009) Discovery and devel-
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agents. J Med Chem;52:2629–2651.
5. Soumik S., Dhanasekaran K., Partha P.K., Tapas K.K.,
Chandrabhas N. (2013) Surface enhanced Raman
spectroscopy of Aurora kinases: direct, ultrasensitive
detection of autophosphorylation. RSC Adv;3:4221–
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6. Karthigeyan D., Siddhanta S., Kishore A.H., Perumal
ꢀ
S.S., Agren H., Sudevan S., Bhat A.V., Balasubra-
manyam K., Subbegowda R.K., Kundu T.K., Narayana
C. (2014) SERS and MD simulation studies of a kinase
inhibitor demonstrate the emergence of a potential
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orescence microscope to perform surface enhanced
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8. Nowakowski J., Cronin C.N., McRee D.E., Knuth
M.W., Nelson C.G., Pavletich N.P., Rogers J., Sang
B.C., Scheibe D.N., Swanson R.V., Thompson D.A.
(2002) Structures of the cancer-related Aurora-A, FAK,
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Acknowledgments
9
. Elkins J.M., Santaguida S., Musacchio A., Knapp S.
(2012) Crystal structure of human Aurora B in complex
with INCENP and VX-680. J Med Chem;55:7841–
7848.
T.K.K. acknowledges JNCASR (Govt of India) and the
financial support of Department of Biotechnology, Grant
BT/01/CEIB/10/III/01, and J. C. Bose National Fellowship.
D.K. acknowledges Council of Scientific and Industrial
Research Senior Research Fellowship.
10. Frisch M.J., Trucks G.W., Schlegel H.B., Scuseria
G.E., Robb M.A., Cheeseman J.R., Montgomery J.A.
Jr. et al. (2004) Gaussian 03, Revision C.02. Walling-
ford, CT.
Author Contributions
11. Morris G.M., Huey R., Lindstrom W.W, Sanner M.F.,
Belew R.K., Goodsell D.S., Olson A.J. (2004)
AutoDock4 and AutoDockTools4: automated docking
with selective receptor flexibility. J Comp Chem;30:
2785.
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
1
2. Schrodinger L.L.C. (2010) The PyMOL Molecular
Graphics System, Version 1.3r1.
Conflict of Interest
13. Cheetham G.M.T., Knegtel R.M.A., Coll J.T., Renwick
S.B., Swenson L., Weber P., Lippke J.A., Austen D.A.
(2002) Crystal structure of Aurora-2, an oncogenic ser-
ine/threonine kinase. J Biol Chem;277:42419–42422.
The authors declare no competing financial interest.
1
4. Connelly P.R., Aldape R.A., Bruzzese F.J., Chambers
S.P., Fitzgibbon M.J., Fleming M.A., Itoh S., Livingston
D.J., Navia M.A., Thomson J.A. (1994) Enthalpy of
hydrogen bond formation in a protein-ligand binding
reaction. Proc Natl Acad Sci U S A;91:1964.
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