دورية أكاديمية
Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma.
| العنوان: | Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma. |
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| المؤلفون: | Bronner SM; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: sbronner@mazetx.com., Merrick KA; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Murray J; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Salphati L; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Moffat JG; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Pang J; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Sneeringer CJ; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Dompe N; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Cyr P; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Purkey H; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Boenig GL; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Li J; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Kolesnikov A; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Larouche-Gauthier R; Paraza Pharma, Inc., 2525 Ave. Marie-Curie, Montreal, QC H4S 2E1, Canada., Lai KW; WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China., Shen X; WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China., Aubert-Nicol S; Paraza Pharma, Inc., 2525 Ave. Marie-Curie, Montreal, QC H4S 2E1, Canada., Chen YC; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Cheong J; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Crawford JJ; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Hafner M; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Haghshenas P; Paraza Pharma, Inc., 2525 Ave. Marie-Curie, Montreal, QC H4S 2E1, Canada., Jakalian A; Paraza Pharma, Inc., 2525 Ave. Marie-Curie, Montreal, QC H4S 2E1, Canada., Leclerc JP; Paraza Pharma, Inc., 2525 Ave. Marie-Curie, Montreal, QC H4S 2E1, Canada., Lim NK; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., O'Brien T; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Plise EG; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Shalan H; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Sturino C; Paraza Pharma, Inc., 2525 Ave. Marie-Curie, Montreal, QC H4S 2E1, Canada., Wai J; WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China., Xiao Y; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Yin J; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Zhao L; Paraza Pharma, Inc., 2525 Ave. Marie-Curie, Montreal, QC H4S 2E1, Canada., Gould S; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Olivero A; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States., Heffron TP; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: heffron.timothy@gene.com. |
| المصدر: | Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Aug 15; Vol. 29 (16), pp. 2294-2301. Date of Electronic Publication: 2019 Jun 26. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Elsevier Science Ltd Original Publication: Oxford ; New York : Pergamon Press, c1991- |
| مواضيع طبية MeSH: | Drug Design*, Antineoplastic Agents/*pharmacology , Brain Neoplasms/*drug therapy , Cyclin-Dependent Kinase 4/*antagonists & inhibitors , Cyclin-Dependent Kinase 6/*antagonists & inhibitors , Glioblastoma/*drug therapy , Protein Kinase Inhibitors/*pharmacology, Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase 6/metabolism ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Humans ; MCF-7 Cells ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Structure-Activity Relationship |
| مستخلص: | CDK4 and CDK6 are kinases with similar sequences that regulate cell cycle progression and are validated targets in the treatment of cancer. Glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease. Abemaciclib, ribociclib, and palbociclib are approved CDK4/6 inhibitors for the treatment of HR+/HER2- breast cancer, but these drugs are not expected to show strong activity in brain tumors due to poor blood brain barrier penetration. Herein, we report the identification of a brain-penetrant CDK4/6 inhibitor derived from a literature molecule with low molecular weight and topological polar surface area (MW = 285 and TPSA = 66 Å 2 ), but lacking the CDK2/1 selectivity profile due to the absence of a basic amine. Removal of a hydrogen bond donor via cyclization of the pyrazole allowed for the introduction of basic and semi-basic amines, while maintaining in many cases efflux ratios reasonable for a CNS program. Ultimately, a basic spiroazetidine (cpK (Copyright © 2019 Elsevier Ltd. All rights reserved.) |
| معلومات مُعتمدة: | P41 GM103393 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: Brain penetration; CDK4; CDK6; Glioblastoma; Kinase |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Protein Kinase Inhibitors) EC 2.7.11.22 (CDK4 protein, human) EC 2.7.11.22 (CDK6 protein, human) EC 2.7.11.22 (Cyclin-Dependent Kinase 4) EC 2.7.11.22 (Cyclin-Dependent Kinase 6) |
| تواريخ الأحداث: | Date Created: 20190717 Date Completed: 20200922 Latest Revision: 20200922 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.bmcl.2019.06.021 |
| PMID: | 31307887 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1464-3405 |
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| DOI: | 10.1016/j.bmcl.2019.06.021 |