2
296 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 10
Letters
References
R. A.; Gramling-Evans, E. E.; Zinker, B. A.; Mika, A. K.; Nguyen,
P. T.; Oltersdorf, T.; Rosenberg, S. H.; Li, Q.; Giranda, V. L. Potent
and selective inhibitors of Akt kinases slow the progress of tumors
in vivo. Mol. Cancer Ther. 2005, 4, 977-986.
(
(
(
1) Brazil, D. P.; Yang, Z. Z.; Hemmings, B. A. Advances in protein
kinase B signalling: AKTion on multiple fronts. Trends Biochem.
Sci. 2004, 29, 233-242.
(
12) Collins, I.; Caldwell, J.; Fonseca, T.; Donald, A.; Bavetsias, V.;
Hunter, L. J.; Garrett, M. D.; Rowlands, M. G.; Aherne, G. W.;
Davies, T. G.; Berdini, V.; Woodhead, S. J.; Davis, D.; Seavers, L.
C.; Wyatt, P. G.; Workman, P.; McDonald, E. Structure-based design
of isoquinoline-5-sulfonamide inhibitors of protein kinase B. Bioorg.
Med. Chem. 2006, 14, 1255-1273.
(13) Davies, T. G.; Verdonk, M. L.; Graham, B.; Saalau-Bethell, S.;
Hamlett, C. C.; McHardy, T.; Collins, I.; Garrett, M. D.; Workman,
P.; Woodhead, S. J.; Jhoti, H.; Barford, D. A structural comparison
of inhibitor binding to PKB, PKA, and PKA-PKB chimera. J. Mol.
Biol. 2007, 367, 882-894.
(14) Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R. Fragment-based
lead discovery. Nat. ReV. Drug DiscoVery 2004, 3, 660-672.
(15) Erlanson, D. A.; McDowell, R. S.; O’Brien, T. Fragment-based drug
discovery. J. Med. Chem. 2004, 47, 3463-3482.
(16) Hartshorn, M. J.; Murray, C. W.; Cleasby, A.; Frederickson, M.;
Tickle, I. J.; Jhoti, H. Fragment-based lead discovery using X-ray
crystallography. J. Med. Chem 2005, 48, 403-413.
2) Hill, M. M.; Hemmings, B. A. Inhibition of protein kinase B/Akt.
Implications for cancer therapy. Pharmacol. Ther. 2002, 93, 243-
251.
3) Barnett, S. F.; Bilodeau, M. T.; Lindsley, C. W. The Akt/PKB family
of protein kinases: A review of small molecule inhibitors and
progress towards target validation. Curr. Top. Med. Chem. 2005, 5,
1
09-125.
(
4) Li, Q.; Zhu, G. D. Targeting serine/threonine protein kinase B/Akt
and cell-cycle checkpoint kinases for treating cancer. Curr. Top. Med.
Chem. 2002, 2, 939-971.
5) Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-kinase AKT
pathway in human cancer. Nat. ReV. Cancer 2002, 2, 489-501.
6) Yang, L.; Dan, H. C.; Sun, M.; Liu, Q.; Sun, X. m.; Feldman, R. I.;
Hamilton, A. D.; Polokoff, M.; Nicosia, S. V.; Herlyn, M.; Sebti, S.
M.; Cheng, J. Q. Akt/protein kinase B signaling inhibitor-2, a
selective small molecule inhibitor of Akt signaling with antitumor
activity in cancer cells overexpressing Akt. Cancer Res. 2004, 64,
(
(
(
17) Mooij, W. T.; Hartshorn, M. J.; Tickle, I. J.; Sharff, A. J.; Verdonk,
M. L.; Jhoti, H. Automated protein-ligand crystallography for
structure-based drug design. ChemMedChem 2006, 1, 827-838.
18) Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: A useful
metric for lead selection. Drug DiscoVery Today 2004, 9, 430-431.
19) Kuntz, I. D.; Chen, K.; Sharp, K. A.; Kollman, P. A. The maximal
affinity of ligands. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 9997-
4
394-4399.
(
(
(
7) Breitenlechner, C. B.; Friebe, W. G.; Brunet, E.; Werner, G.; Graul,
K.; Thomas, U.; Kunkele, K. P.; Schafer, W.; Gassel, M.; Bossem-
eyer, D.; Huber, R.; Engh, R. A.; Masjost, B. Design and crystal
structures of protein kinase B-selective inhibitors in complex with
protein kinase A and mutants. J. Med. Chem. 2005, 48, 163-170.
8) Lin, X.; Murray, J. M.; Rico, A. C.; Wang, M. X.; Chu, D. T.; Zhou,
Y.; Del Rosario, M.; Kaufman, S.; Ma, S.; Fang, E.; Crawford, K.;
Jefferson, A. B. Discovery of 2-pyrimidyl-5-amidothiophenes as
potent inhibitors for AKT: Synthesis and SAR studies. Bioorg. Med.
Chem Lett. 2006, 16, 4163-4168.
(
(
10002.
(
20) Donald, A.; McHardy, T.; Rowlands, M. G.; Hunter, L.-J. K.; Davies,
T. G.; Berdini, V.; Boyle, R. G.; Aherne, G. W.; Garrett, M. D.;
Collins, I. Rapid evolution of 6-phenylpurine inhibitors of protein
kinase B through structure-based design. J. Med. Chem. 2007, 50,
9) Woods, K. W.; Fischer, J. P.; Claiborne, A.; Li, T.; Thomas, S. A.;
Zhu, G. D.; Diebold, R. B.; Liu, X.; Shi, Y.; Klinghofer, V.; Han, E.
K.; Guan, R.; Magnone, S. R.; Johnson, E. F.; Bouska, J. J.; Olson,
A. M.; de Jong, R.; Oltersdorf, T.; Luo, Y.; Rosenberg, S. H.;
Giranda, V. L.; Li, Q. Synthesis and SAR of indazole-pyridine based
protein kinase B/Akt inhibitors. Bioorg. Med. Chem 2006, 14, 6832-
2289-2292.
(
21) Free, S. M.; Wilson, J. W. A mathematical contribution to structure-
activity studies. J. Med. Chem. 1964, 7, 395-399.
(
22) Murray, C. W.; Verdonk, M. L. The consequences of translational
and rotational entropy lost by small molecules on binding to proteins.
J. Comput.-Aided Mol. Des 2002, 16, 741-753.
6846.
(
23) Rejto, P. A.; Verkhivker, G. M. Unraveling principles of lead
discovery: From unfrustrated energy landscapes to novel molecular
anchors. Proc. Natl. Acad. Sci. U.S.A 1996, 93, 8945-8950.
24) Ciulli, A.; Williams, G.; Smith, A. G.; Blundell, T. L.; Abell, C.
Probing hot spots at protein-ligand binding sites: A fragment-based
approach using biophysical methods. J. Med. Chem. 2006, 49,
(
10) Yang, J.; Cron, P.; Good, V. M.; Thompson, V.; Hemmings, B. A.;
Barford, D. Crystal structure of an activated Akt/protein kinase B
ternary complex with GSK3-peptide and AMP-PNP. Nat. Struct.
Biol. 2002, 9, 940-944.
11) Luo, Y.; Shoemaker, A. R.; Liu, X.; Woods, K. W.; Thomas, S. A.;
De Jong, R.; Han, E. K.; Li, T.; Stoll, V. S.; Powlas, J. A.; Oleksijew,
A.; Mitten, M. J.; Shi, Y.; Guan, R.; McGonigal, T. P.; Klinghofer,
V.; Johnson, E. F.; Leverson, J. D.; Bouska, J. J.; Mamo, M.; Smith,
(
(
4992-5000.
JM070091B