دورية أكاديمية
The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition.
| العنوان: | The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition. |
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| المؤلفون: | Chen YK; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Kanouni T; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Arnold LD; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Cox JM; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Gardiner E; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Grandinetti K; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Jiang P; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Kaldor SW; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Lee C; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Li C; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Martin ES; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Miller N; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Murphy EA; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Timple N; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Tyhonas JS; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Vassar A; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Wang TS; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Williams R; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Yuan D; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States., Kania RS; Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2024 Feb 08; Vol. 67 (3), pp. 1747-1757. Date of Electronic Publication: 2024 Jan 17. |
| 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: | Proto-Oncogene Proteins B-raf* , Melanoma*/pathology, Humans ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Cell Line, Tumor ; MAP Kinase Signaling System ; Mutation |
| مستخلص: | RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAF V600E mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues. Recently, significant attention has turned to targeting RAF alterations that activate dimeric signaling (class II and III BRAF and NRAS). However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib ( 15 ), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations. |
| المشرفين على المادة: | EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) 0 (Protein Kinase Inhibitors) |
| تواريخ الأحداث: | Date Created: 20240117 Date Completed: 20240214 Latest Revision: 20240214 |
| رمز التحديث: | 20240214 |
| DOI: | 10.1021/acs.jmedchem.3c01830 |
| PMID: | 38230963 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.3c01830 |