Abstract：
:USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by free energy perturbation (FEP+) calculations. This led to the discovery of compound 41, a highly potent, selective, and orally bioavailable USP7 inhibitor. In xenograft studies, compound 41 demonstrated tumor growth inhibition in both p53 wildtype and p53 mutant cancer cell lines, demonstrating that USP7 inhibitors can suppress tumor growth through multiple different pathways.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Leger PR,Hu DX,Biannic B,Bui M,Han X,Karbarz E,Maung J,Okano A,Osipov M,Shibuya GM,Young K,Higgs C,Abraham B,Bradford D,Cho C,Colas C,Jacobson S,Ohol YM,Pookot D,Rana P,Sanchez J,Shah N,Sun M,Wong S,Brocksdoi
10.1021/acs.jmedchem.0c00245subject
Has Abstractpub_date
2020-05-28 00:00:00pages
5398-5420issue
10eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章abstract：:Water soluble 2'-taxol poly(ethylene glycol) (PEG) esters have been synthesized and shown to function in vitro as prodrugs. However, in vivo experiments clearly establish that in order for these prodrugs to behave in a predictable fashion, the molecular weight of PEG must be of such magnitude so as to maintain a t1/2(...
journal_title：Journal of medicinal chemistry
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更新日期：1998-01-01 00:00:00
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pub_type： 杂志文章
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pub_type： 杂志文章
doi：10.1021/jm00364a032
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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更新日期：1975-11-01 00:00:00
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更新日期：2010-09-09 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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更新日期：1981-01-01 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00123a012
更新日期：1989-03-01 00:00:00
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pub_type： 杂志文章
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更新日期：2005-06-02 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00088a002
更新日期：1992-05-15 00:00:00
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journal_title：Journal of medicinal chemistry
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更新日期：2013-11-27 00:00:00
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journal_title：Journal of medicinal chemistry
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journal_title：Journal of medicinal chemistry
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journal_title：Journal of medicinal chemistry
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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更新日期：2005-10-20 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00117a015
更新日期：1988-09-01 00:00:00
