2292 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 10
Letters
Gassel, M.; Bossemeyer, 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.
6-phenylpurine scaffold. The lead compound 20 shows potent
enzyme inhibition, appropriate cellular activity, and has tractable
physicochemical properties consistent with further optimization.
The evolution of 2 to 16 and 20 shows how potent inhibitors
of PKBâ can be derived from an understanding of the PKB/
PKA pharmacophore. Selectivity for inhibition of PKB over
PKA may be desirable, as PKA activity has been found to be
both oncogenic and tumor-suppressing, dependent on cellular
context.26,27 To introduce this, it will be necessary to consider
more closely the differences between PKB and PKA.16
(10) Burns, S.; Travers, J.; Collins, I.; Rowlands, M. G.; Newbatt, Y.;
Thompson, N.; Garrett, M. D.; Workman, P.; Aherne, G. W.
Identification of small molecule inhibitors of protein kinase B (PKB)
in an AlphaScreen high-throughput screen. J. Biomol. Screening 2006,
11, 822-827.
(11) Collins, I.; Caldwell, J.; Fonseca, T.; Donald, A.; Bavetsias, V.;
Rowlands, M. G.; Hunter, L-J. K.; Garrett, M. D.; Davies, T. G.;
Berdini, V.; Woodhead, S.; Davis, D.; Seavers, L. C. A.; Wyatt, P.
G.; McDonald, E. Structure-based design of isoquinoline-5-sulfona-
mide inhibitors of protein kinase B. Bioorg. Med. Chem. 2006, 14,
1255-1273.
(12) Reuveni, H.; Livnah, N.; Geiger, T.; Klein, S.; Ohne, O.; Cohen, I.;
Benhar, M.; Gellerman, G.; Levitski, A. Toward a PKB inhibitor:
Modification of a selective PKA inhibitor by rational design.
Biochemistry 2002, 41, 10304-10314.
(13) Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R. Fragment-based
lead discovery. Nat. ReV. Drug DiscoVery 2004, 8, 660-672.
(14) 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.
Acknowledgment. This work was supported by Cancer
Research UK [CUK] Grant Number C309/A2187. The authors
thank B. Graham and S. Saalau-Bethell for protein purification,
W. Blakemore for assistance with PKA-PKB crystallography,
and A. Mirza and M. Richards for assistance with compound
characterization.
Supporting Information Available: Experimental details for
the preparation of 13, 14, 16, 18, and 20, experimental details for
pGSK3â ELISA and SRB cellular assays, and X-ray crystallography
statistics (2, 6, 13, 20). This material is available free of charge
(15) Gassell, M.; Breitenlechner, C. B.; Ruger, P.; Jucknischke, U.;
Schneider, T.; Huber, R.; Bossemeyer, D.; Engh, R. A. Mutants of
protein kinase A that mimic the ATP-binding site of protein kinase
B (AKT). J. Mol. Biol. 2003, 329, 1021-1034.
(16) 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.
(17) Havelkova, M.; Hocek, M.; Cesnek, M.; Dvorak, D. The Suzuki-
Miyaura cross-coupling reactions of 6-halopurines with boronic acids
leading to 6-aryl- and 6-phenylpurines. Synlett 1999, 1145-1147.
(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) Liu, G.; Cogan, D. A.; Ellman, J. A. Catalytic asymmetric synthesis
of tert-butanesulfinamide. Application to the asymmetric synthesis
of amines. J. Am. Chem. Soc. 1997, 119, 9913-9914.
(20) ClogP and TPSA calculated using ChemDraw Ultra 10.0; Cam-
bridgeSoft: Cambridge, MA, 2007.
(21) Amschler, U.; Schultz, O. E. Halogen derivatives of epinephrine and
isoproterenol. Arzneim.-Forsch. 1972, 22, 2095-2096.
(22) Berdini, V.; Boyle, R. G.; Saxty, G.; Verdonk, M. L.; Woodhead, S.
J.; Wyatt, P. G.; Sore, H. F.; Caldwell, J.; Collins, I.; Da Fonseca,
T. F.; Donald, A. PCT Intl. Pat. Appl. 046023; Chem. Abstr. 2006,
144, 450718.
(23) Saxty, G.; Woodhead, S. J.; Berdini, V.; Davies, T. G.; Verdonk,
M. L.; Wyatt, P. G.; Boyle, R. G.; Barford, D.; Downham, R.; Garrett,
M. D.; Carr, R. A. Identification of novel inhibitors of protein kinase
B using fragment-based lead discovery. J. Med. Chem. 2007, 50,
2293-2296.
(24) Garrett, M. D.; Hunter, L. J.; Faria Da Fonseca, T.; Caldwell, J.;
Rowlands, M. G.; Hardcastle, A.; Collins, I.; McDonald, E.;
Thompson, N.; Workman, P. 322. Novel isoquinoline-5-sulfonamides
as biochemical and cellular inhibitors of PKB/Akt. Eur. J. Cancer
Suppl. 2004, 2 (8), 98.
(25) Harrington, L. S.; Findlay, G. M.; Gray, A.; Tolkacheva, T.; Wigfield,
S.; Rebholz, H.; Barnett, J.; Leslie, N. R.; Cheng, S.; Shepherd, P.
R.; Gout, I.; Downes, C. P.; Lamb, R. F. The TSC1-2 tumor
suppressor controls insulin-PI3K signaling via regulation of IRS
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(26) Bossis, I.; Stratakis, C. A. Minireview: PRKAR1A: Normal and
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