ACS Medicinal Chemistry Letters
Letter
compound 14 modestly accelerated the degradation of polβ
protein in HeLa cells (data not shown).
ACKNOWLEDGMENTS
We thank Ms. Danielle Fagnani for technical assistance.
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The comparable inhibitory activity toward USP7 and USP47
shown by the compounds in this series in Table 1 is not
surprising given that a phylogenetic comparison of the core
catalytic domains of the USP family reveals that USP47 is one
of the DUBs most closely related to USP7.7 The parallel
inhibition noted has biological significance, as USP7 and
USP47 both play important roles in cell survival, but by
different mechanisms.5,6,8,9
USP7 exerts anti-apoptotic effects by stabilizing HDM2,
thereby destabilizing p53, and also exerts a prosurvival effect by
stabilizing the DNA damage repair protein claspin. In addition
to HDM2, other USP7 substrates have been reported, many of
which function in diverse neoplastic pathways. Thus, a USP7
inhibitor would exert pro-apoptotic, antigrowth effects in p53
wild type and p53 mutant tumors.5
USP47 is an emerging anticancer target, as it regulates base
excision repair via Polβ and also modulates cell growth and
augments the activity of chemotherapeutic agents. Among the
sequelae of stress induced by radiation, mutagens, or other
agents are DNA strand breaks, which are lethal to cells unless
they are repaired. Due to compromised DNA damage repair,
many tumors are highly sensitive to inhibition of DNA repair
enzymes such as Polβ. The cellular level of Polβ is regulated by
a balance between ubiquitylation by E3 ligases decreasing Polβ
concentration and deubiquitylation by USP47, increasing it.
Consistent with this model, treatment of cancer cell lines with
compound 1 or 7 sensitizes them to numerous genotoxic
agents (Kumar, unpublished results).
It is important to note that a dual inhibitor (such as USP7/
USP47), in comparison to compounds that inhibit only one
pathway, likely would have increased single agent or adjuvant
(with genotoxic agents) anticancer efficacy and reduced
susceptibility to the development of drug resistance. We have
identified deubiquitylating enzyme inhibitors that are among
the most selective described so far for these DUBs; some have
sub-micromolar potency as inhibitors of USP7 and USP47. We
discovered that members of this series are inhibitors of USP7
and of USP47 that may act synergistically. In addition, we have
identified the 3,5-dichloropyridine moiety as a potent USP7
pharmacophore. Work is continuing in this area to identify
potential clinical candidates for the treatment of certain cancers.
ABBREVIATIONS
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BER, base excision repair; DUB, deubiquitylating enzyme;
Polβ, DNA polymerase β; HATU, O-(7-azabenzotriazol-1-yl)-
N,N,N′,N′-tetramethyluronium hexafluorophosphate; mCPBA,
3-chloroperoxybenzoic acid
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ASSOCIATED CONTENT
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S
* Supporting Information
Additional SAR tables, synthetic procedures, compound
characterization, biological assay data, and bioassay methods.
This material is available free of charge via the Internet at
AUTHOR INFORMATION
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Corresponding Author
*Phone 610-644-6974, Fax 610-644-8616, E-mail nicholson@
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cyclin D2 inhibition and p21[CIP1] induction. Oncogene 1998, 17,
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Notes
The authors declare the following competing financial
interest(s): J.W., P.C., J.L.M., M.P.K., D.M.M., K.G.S.K.,
S.J.G., M.R.M., and B.N. are or were employees of Progenra,
Inc. when this work was performed. Joseph Weinstock and
William Kingsbury are paid consultants of Progenra, Inc.
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dx.doi.org/10.1021/ml200276j | ACS Med. Chem. Lett. 2012, 3, 789−792