دورية أكاديمية
Privileged Structures and Polypharmacology within and between Protein Families.
| العنوان: | Privileged Structures and Polypharmacology within and between Protein Families. |
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| المؤلفون: | Meyers J; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Chessum NEA; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Ali S; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Mok NY; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Wilding B; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Pasqua AE; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Rowlands M; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Tucker MJ; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Evans LE; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Rye CS; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., O'Fee L; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Le Bihan YV; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Burke R; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Carter M; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Workman P; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Blagg J; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Brown N; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., van Montfort RLM; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Jones K; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom., Cheeseman MD; Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, United Kingdom. |
| المصدر: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Nov 16; Vol. 9 (12), pp. 1199-1204. Date of Electronic Publication: 2018 Nov 16 (Print Publication: 2018). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: eCollection Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society |
| مستخلص: | Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 ( 1 ) and the pirin ligand CCT245232 ( 2 ), to establish methodology to elucidate their secondary protein targets. Using computational pocket-based analysis, we discovered intrafamily polypharmacology for our kinase inhibitor, despite little overall sequence identity. The interfamily polypharmacology of 2 with B-Raf was used to discover a novel pirin ligand from a very small but privileged compound library despite no apparent ligand or binding site similarity. Our data demonstrates that in areas of drug discovery where intrafamily polypharmacology is often an issue, ligand dissimilarity cannot necessarily be used to assume different off-target profiles and that understanding interfamily polypharmacology will be important in the future to reduce the risk of idiopathic toxicity and in the design of screening libraries. Competing Interests: The authors declare the following competing financial interest(s): The authors are employees/students of ICR and ICR has a commercial interest in inhibitors of the HSF1 pathway, CDKs and BRAF. The ICR operates a Rewards to Discoverers scheme. |
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| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; 22897 United Kingdom CRUK_ Cancer Research UK |
| تواريخ الأحداث: | Date Created: 20190108 Latest Revision: 20240214 |
| رمز التحديث: | 20240214 |
| مُعرف محوري في PubMed: | PMC6295861 |
| DOI: | 10.1021/acsmedchemlett.8b00364 |
| PMID: | 30613326 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1948-5875 |
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| DOI: | 10.1021/acsmedchemlett.8b00364 |