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Title: Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors

Journal Article · · ACS Medicinal Chemistry Letters
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  1. Merck Research Lab., Kenilworth, NJ (United States)
  2. Merck Research Lab., Boston, MA (United States)
+ Show Author Affiliations

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23–ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1404955
Journal Information:
ACS Medicinal Chemistry Letters, Vol. 7, Issue 3; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 13 works
Citation information provided by
Web of Science

References (26)

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Unleashing the power of p53: lessons from mice and men journal January 2006
Awakening guardian angels: drugging the p53 pathway journal December 2009
MDM2, MDMX and p53 in oncogenesis and cancer therapy journal January 2013
Small-Molecule Inhibitors of the MDM2–p53 Protein–Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment: Miniperspective journal November 2014
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Small-molecule inhibitors of the p53-HDM2 interaction for the treatment of cancer journal November 2008
A Potent Small-Molecule Inhibitor of the MDM2–p53 Interaction (MI-888) Achieved Complete and Durable Tumor Regression in Mice journal June 2013
Rational Design and Binding Mode Duality of MDM2–p53 Inhibitors journal May 2013
Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011 – present) journal January 2013
Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development journal January 2014
Selective and Potent Morpholinone Inhibitors of the MDM2–p53 Protein–Protein Interaction journal March 2014
Substituted piperidines as HDM2 inhibitors journal February 2014
Pivotal Role of an Aliphatic Side Chain in the Development of an HDM2 Inhibitor journal February 2014
Core modification of substituted piperidines as Novel inhibitors of HDM2–p53 protein–protein interaction journal April 2014
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Cited By (4)

Chalcogen Bonding in Protein−Ligand Complexes: PDB Survey and Quantum Mechanical Calculations journal July 2018
Inhibiting mechanism of small molecule toward the p53-MDM2 interaction: A molecular dynamic exploration journal July 2018
BindingDB Entry 50047479: Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors. dataset January 2017
Identification of Kinases Responsible for p53-Dependent Autophagy journal May 2019

Figures / Tables (14)

Figure 2(p. 2)figure Figure 2
Figure 1(p. 2)figure Figure 1
Figure 3(p. 2)figure Figure 3
Scheme 1(p. 2)figure Scheme 1
Scheme 2(p. 2)figure Scheme 2
Figure 4(p. 3)figure Figure 4
Table 1(p. 3)table Table 1
Table 2(p. 3)table Table 2
Figure 5(p. 4)figure Figure 5
Figure 6(p. 4)figure Figure 6
Table 3(p. 4)table Table 3
Table 4(p. 4)table Table 4
Figure 7(p. 5)figure Figure 7
Figure 8(p. 5)figure Figure 8

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
HDM2
p53
protein−protein interaction
cancer