A
107(1):413–418.
https://doi.org/10.
1073/pnas.0902225107
10. Saupe J, Roske Y, Schillinger C, Kamdem N,
Radetzki S, Diehl A, Oschkinat H, Krause G,
Heinemann U, Rademann J (2011) Discovery,
structure-activity relationship studies, and crystal structure of nonpeptide inhibitors bound to
the Shank3 PDZ domain. ChemMedChem 6
(8):1411–1422. https://doi.org/10.1002/
cmdc.201100094
11. Grandy D, Shan J, Zhang X, Rao S, Akunuru S,
Li H, Zhang Y, Alpatov I, Zhang XA, Lang RA,
Shi DL, Zheng JJ (2009) Discovery and characterization of a small molecule inhibitor of the
PDZ domain of dishevelled. J Biol Chem 284
(24):16256–16263.
https://doi.org/10.
1074/jbc.M109.009647
12. Patra CR, Rupasinghe CN, Dutta SK,
Bhattacharya S, Wang E, Spaller MR, Mukhopadhyay D (2012) Chemically modified peptides targeting the PDZ domain of GIPC as a
therapeutic approach for cancer. ACS Chem
Biol
7(4):770–779.
https://doi.org/10.
1021/cb200536r
13. Kegelman TP, Wu B, Das SK, Talukdar S,
Beckta JM, Hu B, Emdad L, Valerie K,
Sarkar D, Furnari FB, Cavenee WK, Wei J,
Purves A, De SK, Pellecchia M, Fisher PB
(2017) Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin. Proc
Natl Acad Sci U S A 114(2):370–375.
https://doi.org/10.1073/pnas.1616100114
14. Bach A, Chi CN, Olsen TB, Pedersen SW,
Røder MU, Pang GF, Clausen RP, Jemth P,
Strømgaard K (2008) Modified peptides as
potent inhibitors of the postsynaptic density95/N-methyl-D-aspartate receptor interaction. J Med Chem 51(20):6450–6459.
https://doi.org/10.1021/jm800836w
15. Bach A, Eildal JN, Stuhr-Hansen N,
Deeskamp R, Gottschalk M, Pedersen SW,
Kristensen AS, Strømgaard K (2011) Cellpermeable and plasma-stable peptidomimetic
inhibitors of the postsynaptic density-95/Nmethyl-D-aspartate receptor interaction. J
Med Chem 54(5):1333–1346. https://doi.
org/10.1021/jm1013924
16. Bach A, Clausen BH, Møller M, Vestergaard B,
Chi CN, Round A, Sørensen PL, Nissen KB,
Kastrup JS, Gajhede M, Jemth P, Kristensen
AS, Lundstro ¨m P, Lambertsen KL, Strømgaard
K (2012) A high-affinity, dimeric inhibitor of
PSD-95 bivalently interacts with PDZ1-2 and
protects against ischemic brain damage. Proc
Natl Acad Sci U S A 109(9):3317–3322.
https://doi.org/10.1073/pnas.1113761109
17. Wells JA, McClendon CL (2007) Reaching for
high-hanging fruit in drug discovery at
protein-protein interfaces. Nature 450
(7172):1001–1009.
https://doi.org/10.
1038/nature06526
18. Morelli X, Bourgeas R, Roche P (2011) Chemical and structural lessons from recent successes
in protein-protein interaction inhibition
(2P2I). Curr Opin Chem Biol 15
(4):475–481.
https://doi.org/10.1016/j.
cbpa.2011.1005.1024
19. Bourgeas R, Basse MJ, Morelli X, Roche P
(2010) Atomic analysis of protein-protein
interfaces with known inhibitors: the 2P2I
database. PLoS One 5(3):e9598. https://doi.
org/10.1371/journal.pone.0009598
20. Chen X, Longgood JC, Michnoff C, Wei S,
Frantz DE, Bezprozvanny L (2007) Highthroughput screen for small molecule inhibitors of Mint1-PDZ domains. Assay Drug Dev
Technol 5(6):769–783. https://doi.org/10.
1089/adt.2007.092
21. Hajduk P, Huth J, Fesik S (2005) Druggability
indices for protein targets derived from
NMR-based screening data. J Med Chem 48
(7):2518–2525. https://doi.org/10.1021/
jm049131r
22. Fujii N, Haresco JJ, Novak KA, Stokoe D,
Kuntz ID, Guy RK (2003) A selective irreversible inhibitor targeting a PDZ protein interaction domain. J Am Chem Soc 125
(40):12074–12075.
https://doi.org/10.
1021/ja035540l
23. Ewing TJ, Makino S, Skillman GA, Kuntz ID
(2001) DOCK 4.0: search strategies for automated molecular docking of flexible molecule
databases. J Comput Aided Mol Des 15
(5):411–428
24. Fujii N, Haresco JJ, Novak KA, Gage RM,
Pedemonte N, Stokoe D, Kuntz ID, Guy RK
(2007) Rational design of a nonpeptide general
chemical scaffold for reversible inhibition of
PDZ domain interactions. Bioorg Med Chem
Lett 17(2):549–552. https://doi.org/10.
1016/j.bmcl.2006.10.006
25. Fujii N, You L, Xu Z, Uematsu K, Shan J,
He B, Mikami I, Edmondson LR, Neale G,
Zheng J, Guy RK, Jablons DM (2007) An
antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent
tumor cell growth. Cancer Res 67
(2):573–579.
https://doi.org/10.1158/
0008-5472.CAN-06-2726
26. Mayasundari A, Ferreira AM, He L,
Mahindroo N, Bashford D, Fujii N (2008)
Rational design of the first small-molecule
antagonists of NHERF1/EBP50 PDZ
domains. Bioorg Med Chem Lett 18
Rational Design of PDZ Domain Inhibitors
287
107(1):413–418.
https://doi.org/10.
1073/pnas.0902225107
10. Saupe J, Roske Y, Schillinger C, Kamdem N,
Radetzki S, Diehl A, Oschkinat H, Krause G,
Heinemann U, Rademann J (2011) Discovery,
structure-activity relationship studies, and crystal structure of nonpeptide inhibitors bound to
the Shank3 PDZ domain. ChemMedChem 6
(8):1411–1422. https://doi.org/10.1002/
cmdc.201100094
11. Grandy D, Shan J, Zhang X, Rao S, Akunuru S,
Li H, Zhang Y, Alpatov I, Zhang XA, Lang RA,
Shi DL, Zheng JJ (2009) Discovery and characterization of a small molecule inhibitor of the
PDZ domain of dishevelled. J Biol Chem 284
(24):16256–16263.
https://doi.org/10.
1074/jbc.M109.009647
12. Patra CR, Rupasinghe CN, Dutta SK,
Bhattacharya S, Wang E, Spaller MR, Mukhopadhyay D (2012) Chemically modified peptides targeting the PDZ domain of GIPC as a
therapeutic approach for cancer. ACS Chem
Biol
7(4):770–779.
https://doi.org/10.
1021/cb200536r
13. Kegelman TP, Wu B, Das SK, Talukdar S,
Beckta JM, Hu B, Emdad L, Valerie K,
Sarkar D, Furnari FB, Cavenee WK, Wei J,
Purves A, De SK, Pellecchia M, Fisher PB
(2017) Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin. Proc
Natl Acad Sci U S A 114(2):370–375.
https://doi.org/10.1073/pnas.1616100114
14. Bach A, Chi CN, Olsen TB, Pedersen SW,
Røder MU, Pang GF, Clausen RP, Jemth P,
Strømgaard K (2008) Modified peptides as
potent inhibitors of the postsynaptic density95/N-methyl-D-aspartate receptor interaction. J Med Chem 51(20):6450–6459.
https://doi.org/10.1021/jm800836w
15. Bach A, Eildal JN, Stuhr-Hansen N,
Deeskamp R, Gottschalk M, Pedersen SW,
Kristensen AS, Strømgaard K (2011) Cellpermeable and plasma-stable peptidomimetic
inhibitors of the postsynaptic density-95/Nmethyl-D-aspartate receptor interaction. J
Med Chem 54(5):1333–1346. https://doi.
org/10.1021/jm1013924
16. Bach A, Clausen BH, Møller M, Vestergaard B,
Chi CN, Round A, Sørensen PL, Nissen KB,
Kastrup JS, Gajhede M, Jemth P, Kristensen
AS, Lundstro ¨m P, Lambertsen KL, Strømgaard
K (2012) A high-affinity, dimeric inhibitor of
PSD-95 bivalently interacts with PDZ1-2 and
protects against ischemic brain damage. Proc
Natl Acad Sci U S A 109(9):3317–3322.
https://doi.org/10.1073/pnas.1113761109
17. Wells JA, McClendon CL (2007) Reaching for
high-hanging fruit in drug discovery at
protein-protein interfaces. Nature 450
(7172):1001–1009.
https://doi.org/10.
1038/nature06526
18. Morelli X, Bourgeas R, Roche P (2011) Chemical and structural lessons from recent successes
in protein-protein interaction inhibition
(2P2I). Curr Opin Chem Biol 15
(4):475–481.
https://doi.org/10.1016/j.
cbpa.2011.1005.1024
19. Bourgeas R, Basse MJ, Morelli X, Roche P
(2010) Atomic analysis of protein-protein
interfaces with known inhibitors: the 2P2I
database. PLoS One 5(3):e9598. https://doi.
org/10.1371/journal.pone.0009598
20. Chen X, Longgood JC, Michnoff C, Wei S,
Frantz DE, Bezprozvanny L (2007) Highthroughput screen for small molecule inhibitors of Mint1-PDZ domains. Assay Drug Dev
Technol 5(6):769–783. https://doi.org/10.
1089/adt.2007.092
21. Hajduk P, Huth J, Fesik S (2005) Druggability
indices for protein targets derived from
NMR-based screening data. J Med Chem 48
(7):2518–2525. https://doi.org/10.1021/
jm049131r
22. Fujii N, Haresco JJ, Novak KA, Stokoe D,
Kuntz ID, Guy RK (2003) A selective irreversible inhibitor targeting a PDZ protein interaction domain. J Am Chem Soc 125
(40):12074–12075.
https://doi.org/10.
1021/ja035540l
23. Ewing TJ, Makino S, Skillman GA, Kuntz ID
(2001) DOCK 4.0: search strategies for automated molecular docking of flexible molecule
databases. J Comput Aided Mol Des 15
(5):411–428
24. Fujii N, Haresco JJ, Novak KA, Gage RM,
Pedemonte N, Stokoe D, Kuntz ID, Guy RK
(2007) Rational design of a nonpeptide general
chemical scaffold for reversible inhibition of
PDZ domain interactions. Bioorg Med Chem
Lett 17(2):549–552. https://doi.org/10.
1016/j.bmcl.2006.10.006
25. Fujii N, You L, Xu Z, Uematsu K, Shan J,
He B, Mikami I, Edmondson LR, Neale G,
Zheng J, Guy RK, Jablons DM (2007) An
antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent
tumor cell growth. Cancer Res 67
(2):573–579.
https://doi.org/10.1158/
0008-5472.CAN-06-2726
26. Mayasundari A, Ferreira AM, He L,
Mahindroo N, Bashford D, Fujii N (2008)
Rational design of the first small-molecule
antagonists of NHERF1/EBP50 PDZ
domains. Bioorg Med Chem Lett 18
Rational Design of PDZ Domain Inhibitors
287