دورية أكاديمية
Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity.
| العنوان: | Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity. |
|---|---|
| المؤلفون: | Leger PR; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Hu DX; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Biannic B; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Bui M; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Han X; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Karbarz E; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Maung J; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Okano A; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Osipov M; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Shibuya GM; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Young K; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Higgs C; Schrödinger, 120 West 45th Street, New York, New York 10036, United States., Abraham B; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Bradford D; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Cho C; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Colas C; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Jacobson S; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Ohol YM; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Pookot D; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Rana P; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Sanchez J; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Shah N; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Sun M; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Wong S; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Brockstedt DG; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Kassner PD; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Schwarz JB; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States., Wustrow DJ; RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2020 May 28; Vol. 63 (10), pp. 5398-5420. Date of Electronic Publication: 2020 May 06. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Antineoplastic Agents/*administration & dosage , Antineoplastic Agents/*chemistry , Drug Discovery/*methods , Ubiquitin-Specific Peptidase 7/*antagonists & inhibitors , Ubiquitin-Specific Peptidase 7/*chemistry, Administration, Oral ; Animals ; Cell Line, Tumor ; Crystallography, X-Ray/methods ; Humans ; Mice ; Mice, Inbred NOD ; Mice, Nude ; Mice, SCID ; Protein Structure, Tertiary ; Ubiquitin-Specific Peptidase 7/metabolism ; Xenograft Model Antitumor Assays/methods |
| مستخلص: | 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. |
| المشرفين على المادة: | 0 (Antineoplastic Agents) EC 3.4.19.12 (USP7 protein, human) EC 3.4.19.12 (Ubiquitin-Specific Peptidase 7) |
| تواريخ الأحداث: | Date Created: 20200418 Date Completed: 20201023 Latest Revision: 20201023 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/acs.jmedchem.0c00245 |
| PMID: | 32302140 |
| قاعدة البيانات: | MEDLINE |
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