Journal of Medicinal Chemistry
Article
(11) Klein, H. L. The consequences of Rad51 overexpression for
normal and tumor cells. DNA Repair 2008, 7, 686−693.
(12) Hine, C. M.; Seluanov, A.; Gorbunova, V. Use of the Rad51
promoter for targeted anti-cancer therapy. Proc. Natl. Acad. Sci. U.S.A.
2008, 105, 20810−20815.
(13) Connell, P. P.; Jayathilaka, K.; Haraf, D. J.; Weichselbaum, R. R.;
Vokes, E. E.; Lingen, M. W. Pilot study examining tumor expression of
RAD51 and clinical outcomes in human head cancers. Int. J. Oncol.
2006, 28, 1113−1119.
(14) Budke, B.; Logan, H. L.; Kalin, J. H.; Zelivianskaia, A. S.;
Cameron McGuire, W.; Miller, L. L.; Stark, J. M.; Kozikowski, A. P.;
Bishop, D. K.; Connell, P. P. RI-1: a chemical inhibitor of RAD51 that
disrupts homologous recombination in human cells. Nucleic Acids Res.
2012, 40, 7347−7357.
(15) Ishida, T.; Takizawa, Y.; Kainuma, T.; Inoue, J.; Mikawa, T.;
Shibata, T.; Suzuki, H.; Tashiro, S.; Kurumizaka, H. DIDS, a chemical
compound that inhibits RAD51-mediated homologous pairing and
strand exchange. Nucleic Acids Res. 2009, 37, 3367−3376.
(16) Takaku, M.; Kainuma, T.; Ishida-Takaku, T.; Ishigami, S.;
Suzuki, H.; Tashiro, S.; van Soest, R. W.; Nakao, Y.; Kurumizaka, H.
Halenaquinone, a chemical compound that specifically inhibits the
secondary DNA binding of RAD51. Genes Cells 2011, 16, 427−436.
(17) Huang, F.; Motlekar, N. A.; Burgwin, C. M.; Napper, A. D.;
Diamond, S. L.; Mazin, A. V. Identification of specific inhibitors of
human RAD51 recombinase using high-throughput screening. ACS
Chem. Biol. 2011, 6, 628−635.
(18) Huang, F.; Mazina, O. M.; Zentner, I. J.; Cocklin, S.; Mazin, A.
V. Inhibition of homologous recombination in human cells by
targeting RAD51 recombinase. J. Med. Chem. 2012, 55, 3011−3020.
(19) Nomme, J.; Renodon-Corniere, A.; Asanomi, Y.; Sakaguchi, K.;
Stasiak, A. Z.; Stasiak, A.; Norden, B.; Tran, V.; Takahashi, M. Design
of potent inhibitors of human RAD51 recombinase based on BRC
motifs of BRCA2 protein: modeling and experimental validation of a
chimera peptide. J. Med. Chem. 2010, 53, 5782−5791.
(20) Davies, A. A.; Masson, J. Y.; McIlwraith, M. J.; Stasiak, A. Z.;
Stasiak, A.; Venkitaraman, A. R.; West, S. C. Role of BRCA2 in control
of the RAD51 recombination and DNA repair protein. Mol. Cell 2001,
7, 273−282.
(21) Russell, J. S.; Brady, K.; Burgan, W. E.; Cerra, M. A.; Oswald, K.
A.; Camphausen, K.; Tofilon, P. J. Gleevec-mediated inhibition of
Rad51 expression and enhancement of tumor cell radiosensitivity.
Cancer Res. 2003, 63, 7377−7383.
(22) Ito, M.; Yamamoto, S.; Nimura, K.; Hiraoka, K.; Tamai, K.;
Kaneda, Y. Rad51 siRNA delivered by HVJ envelope vector enhances
the anti-cancer effect of cisplatin. J. Gene Med. 2005, 7, 1044−1052.
(23) Jayathilaka, K.; Sheridan, S. D.; Bold, T. D.; Bochenska, K.;
Logan, H. L.; Weichselbaum, R. R.; Bishop, D. K.; Connell, P. P. A
chemical compound that stimulates the human homologous
recombination protein RAD51. Proc. Natl. Acad. Sci. U.S.A. 2008,
105, 15848−15853.
AUTHOR INFORMATION
Corresponding Author
*Phone: (773) 834-8119. Fax: (773) 702-0610. E-mail:
■
Author Contributions
§These authors contributed equally and are listed in alphabet-
ical order
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by funding from the National
Institutes of Health [Grant CA142642-02 2010-2015 to P.P.C.
and A.P.K. (and Douglas K. Bishop); Grant 2T32CA009594 to
B.B.]. We thank Douglas K. Bishop for helpful conversations.
ABBREVIATIONS USED
■
HR, homologous recombination; DSB, double stranded break;
NHEJ, nonhomologous end joining; ICL, interstrand DNA
cross-link; ssDNA, single-stranded DNA; RPA, replication
protein A; MMC, mitomycin C; RI-1, RAD51-inhibitory
compound 1; RI-2, RAD51-inhibitory compound 2; SAR,
structure−activity relationship; SSA, single-strand annealing
REFERENCES
■
(1) Thompson, L. H.; Schild, D. Homologous recombinational repair
of DNA ensures mammalian chromosome stability. Mutat. Res. 2001,
477, 131−153.
(2) Tebbs, R. S.; Zhao, Y.; Tucker, J. D.; Scheerer, J. B.; Siciliano, M.
J.; Hwang, M.; Liu, N.; Legerski, R. J.; Thompson, L. H. Correction of
chromosomal instability and sensitivity to diverse mutagens by a
cloned cDNA of the XRCC3 DNA repair gene. Proc. Natl. Acad. Sci.
U.S.A. 1995, 92, 6354−6358.
(3) Liu, N.; Lamerdin, J. E.; Tebbs, R. S.; Schild, D.; Tucker, J. D.;
Shen, M. R.; Brookman, K. W.; Siciliano, M. J.; Walter, C. A.; Fan, W.;
Narayana, L. S.; Zhou, Z. Q.; Adamson, A. W.; Sorensen, K. J.; Chen,
D. J.; Jones, N. J.; Thompson, L. H. XRCC2 and XRCC3, new human
Rad51-family members, promote chromosome stability and protect
against DNA cross-links and other damages. Mol. Cell 1998, 1, 783−
793.
(4) Takata, M.; Sasaki, M. S.; Tachiiri, S.; Fukushima, T.; Sonoda, E.;
Schild, D.; Thompson, L. H.; Takeda, S. Chromosome instability and
defective recombinational repair in knockout mutants of the five
Rad51 paralogs. Mol. Cell. Biol. 2001, 21, 2858−2866.
(5) Pellegrini, L.; Yu, D. S.; Lo, T.; Anand, S.; Lee, M.; Blundell, T.
L.; Venkitaraman, A. R. Insights into DNA recombination from the
structure of a RAD51-BRCA2 complex. Nature 2002, 420, 287−293.
(6) Conway, A. B.; Lynch, T. W.; Zhang, Y.; Fortin, G. S.; Fung, C.
W.; Symington, L. S.; Rice, P. A. Crystal structure of a Rad51 filament.
Nat. Struct. Mol. Biol. 2004, 11, 791−796.
(7) Vispe, S.; Cazaux, C.; Lesca, C.; Defais, M. Overexpression of
Rad51 protein stimulates homologous recombination and increases
resistance of mammalian cells to ionizing radiation. Nucleic Acids Res.
1998, 26, 2859−2864.
(8) Slupianek, A.; Schmutte, C.; Tombline, G.; Nieborowska-Skorska,
M.; Hoser, G.; Nowicki, M. O.; Pierce, A. J.; Fishel, R.; Skorski, T.
BCR/ABL regulates mammalian RecA homologs, resulting in drug
resistance. Mol. Cell 2001, 8, 795−806.
(9) Bello, V. E.; Aloyz, R. S.; Christodoulopoulos, G.; Panasci, L. C.
Homologous recombinational repair vis-a-vis chlorambucil resistance
in chronic lymphocytic leukemia. Biochem. Pharmacol. 2002, 63,
1585−1588.
(24) Smith, M. E.; Schumacher, F. F.; Ryan, C. P.; Tedaldi, L. M.;
Papaioannou, D.; Waksman, G.; Caddick, S.; Baker, J. R. Protein
modification, bioconjugation, and disulfide bridging using bromoma-
leimides. J. Am. Chem. Soc. 2010, 132, 1960−1965.
(25) Matuszak, N.; Muccioli, G. G.; Labar, G.; Lambert, D. M.
Synthesis and in vitro evaluation of N-substituted maleimide
derivatives as selective monoglyceride lipase inhibitors. J. Med. Chem.
2009, 52, 7410−7420.
(26) Relles, H. M.; Schluenz, R. W. Dichloromaleimide chemistry. I.
Substituent effects on carbon-13 nuclear magnetic resonance and mass
spectra. J. Org. Chem. 1972, 37, 1742−1745.
(27) Walter, M. E.; Mora, C.; Mundstock, K.; de Souza, M. M.; de
Oliveira Pinheiro, A.; Yunes, R. A.; Nunes, R. J. Antinociceptive
properties of chloromaleinimides and their sulphonyl derivatives. Arch.
Pharm. 2004, 337, 1521−4184.
(28) Xu, G.; He, Q.; Yang, B.; Hu, Y. Synthesis and antitumor activity
of novel 4-chloro-3-arylmaleimide derivatives. Lett. Drug Des. Discovery
2009, 6, 51−55.
(10) Hansen, L. T.; Lundin, C.; Spang-Thomsen, M.; Petersen, L. N.;
Helleday, T. The role of RAD51 in etoposide (VP16) resistance in
small cell lung cancer. Int. J. Cancer 2003, 105, 472−479.
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