ACS Combinatorial Science
Research Article
Adrain, C.; Martin, S. J. Executioner caspase-3, -6, and -7 perform distinct,
non-redundant roles during the demolition phase of apoptosis. J. Biol.
Chem. 2001, 276, 7320−6. (d) Sakahira, H.; Enari, M.; Nagata, S.
Cleavage of CAD inhibitor in CAD activation and DNA degradation
during apoptosis. Nature 1998, 391, 96−99.
(4) (a) Hanahan, D.; Weinberg, R. A. The hallmarks of cancer. Cell
2000, 100, 57−70. (b) Hanahan, D.; Weinberg, R. A. Hallmarks of
cancer: the next generation. Cell 2011, 144, 646−74.
(5) Vassilev, L. T.; Vu, B. T.; Graves, B.; Carvajal, D.; Podlaski, F.;
Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi,
N.; Liu, E. A. In vivo activation of the p53 pathway by small-molecule
antagonists of MDM2. Science 2004, 303, 844−8.
(18) Peterson, Q. P.; Hsu, D. C.; Goode, D. R.; Novotny, C. J.;
Totten, R. K.; Hergenrother, P. J. Procaspase-3 activation as an anti-
cancer strategy: Structure−activity relationship of procaspase-activat-
ing compound 1 (PAC-1) and its cellular co-localization with caspase-
3. J. Med. Chem. 2009, 52, 5721−5731.
(19) Charkoudian, L. K.; Pham, D. M.; Franz, K. J. A pro-chelator
triggered by hydrogen peroxide inhibits iron-promoted hydroxyl
radical formation. J. Am. Chem. Soc. 2006, 128, 12424−5.
(20) Peterson, Q. P.; Goode, D. R.; West, D. C.; Ramsey, K. N.; Lee,
J. J. Y.; Hergenrother, P. J. PAC-1 activates procaspase-3 in vitro
through relief of zinc-mediated inhibition. J. Mol. Biol. 2009, 388, 144−
158.
(21) Truong-Tran, A. Q.; Grosser, D.; Ruffin, R. E.; Murgia, C.;
Zalewski, P. D. Apoptosis in the normal and inflamed airway
epithelium: role of zinc in epithelial protection and procaspase-3
regulation. Biochem. Pharmacol. 2003, 66, 1459−1468.
(22) Lucas, P. W.; Schmit, J. M.; Peterson, Q. P.; West, D. C.; Hsu,
D. C.; Novotny, C. J.; Dirikolu, L.; Churchwell, M. I.; Doerge, D. R.;
Garrett, L. D.; Hergenrother, P. J.; Fan, T. M. Pharmacokinetics and
derivation of an anticancer dosing regimen for PAC-1, a preferential
small molecule activator of procaspase-3, in healthy dogs. Invest. New
Drugs 2011, 29, 901−11.
(23) Peterson, Q. P.; Hsu, D. C.; Novotny, C. J.; West, D. C.; Kim,
D.; Schmit, J. M.; Dirikolu, L.; Hergenrother, P. J.; Fan, T. M.
Discovery and canine preclinical assessment of a nontoxic procaspase-
3-activating compound. Cancer Res. 2010, 70, 7232−41.
(24) Hergenrother, P. J.; Putt, K. S.; Sandhorst, J. S.; Peterson, Q. P.;
Fako, V. Compositions and methods including cell death inducers and
procaspase activation. International Patent Application WO 2008/
134474.
(25) Miller, C. E. Hydrogenation with diimide. J. Chem. Educ. 1965,
42, 254−&.
(26) Chang, K. H.; Huang, C. C.; Liu, Y. H.; Hu, Y. H.; Chou, P. T.;
Lin, Y. C. Synthesis of photo-luminescent Zn(II) Schiff base
complexes and its derivative containing Pd(II) moiety. Dalton Trans.
2004, 1731−8.
(27) Peterson, Q. P.; Goode, D. R.; West, D. C.; Botham, R. C.;
Hergenrother, P. J. Preparation of the caspase-3/7 substrate Ac-
DEVD-pNA by solution-phase peptide synthesis. Nat. Protoc. 2010, 5,
294−302.
(6) Oltersdorf, T.; Elmore, S. W.; Shoemaker, A. R.; Armstrong,
R. C.; Augeri, D. J.; Belli, B. A.; Bruncko, M.; Deckwerth, T. L.;
Dinges, J.; Hajduk, P. J.; Joseph, M. K.; Kitada, S.; Korsmeyer, S. J.;
Kunzer, A. R.; Letai, A.; Li, C.; Mitten, M. J.; Nettesheim, D. G.; Ng,
S.; Nimmer, P. M.; O’Connor, J. M.; Oleksijew, A.; Petros, A. M.;
Reed, J. C.; Shen, W.; Tahir, S. K.; Thompson, C. B.; Tomaselli, K. J.;
Wang, B. L.; Wendt, M. D.; Zhang, H. C.; Fesik, S. W.; Rosenberg,
S. H. An inhibitor of Bcl-2 family proteins induces regression of solid
tumours. Nature 2005, 435, 677−681.
(7) Lu, J.; Bai, L.; Sun, H.; Nikolovska-Coleska, Z.; McEachern, D.;
Qiu, S.; Miller, R. S.; Yi, H.; Shangary, S.; Sun, Y.; Meagher, J. L.;
Stuckey, J. A.; Wang, S. SM-164: a novel, bivalent Smac mimetic that
induces apoptosis and tumor regression by concurrent removal of the
blockade of cIAP-1/2 and XIAP. Cancer Res. 2008, 68, 9384−93.
(8) Putt, K. S.; Chen, G. W.; Pearson, J. M.; Sandhorst, J. S.;
Hoagland, M. S.; Kwon, J. T.; Hwang, S. K.; Jin, H.; Churchwell, M. I.;
Cho, M. H.; Doerge, D. R.; Helferich, W. G.; Hergenrother, P. J.
Small-molecule activation of procaspase-3 to caspase-3 as a
personalized anticancer strategy. Nat. Chem. Biol. 2006, 2, 543−550.
(9) Soini, Y.; Paakko, P. Apoptosis and expression of caspases 3, 6
and 8 in malignant non-Hodgkin’s lymphomas. APMIS 1999, 107,
1043−50.
(10) Estrov, Z.; Thall, P. F.; Talpaz, M.; Estey, E. H.; Kantarjian,
H. M.; Andreeff, M.; Harris, D.; Van, Q.; Walterscheid, M.; Kornblau,
S. M. Caspase 2 and caspase 3 protein levels as predictors of survival in
acute myelogenous leukemia. Blood 1998, 92, 3090−7.
(11) Fink, D.; Schlagbauer-Wadl, H.; Selzer, E.; Lucas, T.; Wolff, K.;
Pehamberger, H.; Eichler, H. G.; Jansen, B. Elevated procaspase levels
in human melanoma. Melanoma Res. 2001, 11, 385−93.
(12) Virkajarvi, N.; Paakko, P.; Soini, Y. Apoptotic index and
apoptosis influencing proteins bcl-2, mcl-1, bax and caspases 3, 6 and 8
in pancreatic carcinoma. Histopathology 1998, 33, 432−9.
(13) Persad, R.; Liu, C.; Wu, T. T.; Houlihan, P. S.; Hamilton, S. R.;
Diehl, A. M.; Rashid, A. Overexpression of caspase-3 in hepatocellular
carcinomas. Mod. Pathol. 2004, 17, 861−7.
(14) (a) Tormanen-Napankangas, U.; Soini, Y.; Kahlos, K.; Kinnula,
V.; Paakko, P. Expression of caspases-3, −6 and −8 and their relation
to apoptosis in non-small cell lung carcinoma. Int. J. Cancer 2001, 93,
192−8. (b) Krepela, E.; Prochazka, J.; Liul, X.; Fiala, P.; Kinkor, Z.
Increased expression of Apaf-1 and procaspase-3 and the functionality
of intrinsic apoptosis apparatus in non-small cell lung carcinoma. Biol.
Chem. 2004, 385, 153−68.
(15) (a) O’Donovan, N.; Crown, J.; Stunell, H.; Hill, A. D.;
McDermott, E.; O’Higgins, N.; Duffy, M. J. Caspase 3 in breast cancer.
Clin. Cancer Res. 2003, 9, 738−42. (b) Zapata, J. M.; Krajewska, M.;
Krajewski, S.; Huang, R. P.; Takayama, S.; Wang, H. G.; Adamson, E.;
Reed, J. C. Expression of multiple apoptosis-regulatory genes in human
breast cancer cell lines and primary tumors. Breast Cancer Res. Treat.
1998, 47, 129−40.
(16) Roy, S.; Bayly, C. I.; Gareau, Y.; Houtzager, V. M.; Kargman, S.;
Keen, S. L.; Rowland, K.; Seiden, I. M.; Thornberry, N. A.; Nicholson,
D. W. Maintenance of caspase-3 proenzyme dormancy by an intrinsic
“safety catch” regulatory tripeptide. Proc. Natl. Acad. Sci. U. S. A. 2001,
98, 6132−7.
(17) Wolan, D. W.; Zorn, J. A.; Gray, D. C.; Wells, J. A. Small-
Molecule Activators of a Proenzyme. Science 2009, 326, 853−858.
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