Journal of Medicinal Chemistry
Brief Article
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from activation of the p53 pathway, and in vivo efficacy.
Although the cellular mechanism of action of RG7388 is
identical to that of RG7112, it is much more potent and
selective. RG7388 activates p53 (Figure 6 and SI) at a
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Figure 6. Western blot analysis of the levels of p53 and select target
proteins resulting from the treatment of SJSA cells for 20 h with
Nutlin-3a, RG7112, or RG7388.
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concentration that is an order of magnitude lower than
RG7112. Importantly, this trend extends to the in vivo setting,
where the exposures required for the same levels of efficacy are
much lower for RG7388 (Table 3).
In summary, our studies of this pyrrolidine scaffold led to the
identification of a highly potent and selective MDM2
antagonist, RG7388. The data reported here show that
RG7388 blocks p53−MDM2 binding and effectively activates
the p53 pathway, leading to cell cycle arrest and/or apoptosis in
cell lines expressing wild-type p53 and tumor growth inhibition
or regression of osteosarcoma xenografts in nude mice.
RG7388 is undergoing clinical investigation in solid and
hematological tumors.
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Targeting the MDM2−p53 Protein−Protein Interaction for New
Cancer Therapeutics. Top. Med. Chem. 2012, 8, 57−80.
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(17) Ray-Coquard, I.; Blay, J. Y.; Italiano, A.; Le Cesne, A.; Penel, N.;
Zhi, J.; Heil, F.; Rueger, R.; Graves, B.; Ding, M.; Geho, D.; Middleton,
S. A.; Vassilev, L. T.; Nichols, G. L.; Bui, B. N. Effect of the MDM2
antagonist RG7112 on the P53 pathway in patients with MDM2-
amplified, well-differentiated or dedifferentiated liposarcoma: an
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental section. This material is available free of
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AUTHOR INFORMATION
Corresponding Author
(18) (a) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.;
Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish,
D. A.; Deschamps, J. R.; Wang, S. Structure-based design of potent
non-peptide MDM2 inhibitors. J. Am. Chem. Soc. 2005, 127 (29),
10130−10131. (b) Yu, S.; Qin, D.; Shangary, S.; Chen, J.; Wang, G.;
Ding, K.; McEachern, D.; Qiu, S.; Nikolovska-Coleska, Z.; Miller, R.;
Kang, S.; Yang, D.; Wang, S. Potent and Orally Active Small-Molecule
Inhibitors of the MDM2−p53 Interaction. J. Med. Chem. 2009, 52
(24), 7970−7973.
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Author Contributions
⊥These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
(19) (a) Popowicz, G. M.; Czarna, A.; Wolf, S.; Wang, K.; Wang, W.;
ACKNOWLEDGMENTS
SFC purification by Theodore Lambros, detailed H and NOE
NMR analysis for determination of stereochemical config-
uration by Gino Sasso, high resolution mass spectrometry by
George Perkins, and insightful discussion with Binh Vu are
gratefully acknowledged.
Domling, A.; Holak, T. A. Structures of low molecular weight
̈
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1
inhibitors bound to MDMX and MDM2 reveal new approaches for
p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle 2010, 9 (5),
1104−1111. (b) Shu, L.; Li, Z.; Gu, C.; Fishlock, D. Synthesis of a
Spiroindolinone Pyrrolidinecarboxamide MDM2 Antagonist. Org.
Process Res. Dev. 2013, 17 (2), 247−256. (c) Zhao, Y.; Liu, L.; Sun,
W.; Lu, J.; McEachern, D.; Li, X.; Yu, S.; Bernard, D.; Ochsenbein, P.;
Ferey, V.; Carry, J.-C.; Deschamps, J. R.; Sun, D.; Wang, S.
Diastereomeric Spirooxindoles as Highly Potent and Efficacious
MDM2 Inhibitors. J. Am. Chem. Soc. 2013, 135 (19), 7223−7234.
(d) Carry, J.-C.; Garcia-Echeverria, C. Inhibitors of the p53/HDM2
protein−protein interaction-path to the clinic. Bioorg. Med. Chem. Lett.
2013, 23, 2480−2485.
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