دورية أكاديمية
Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer.
| العنوان: | Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer. |
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| المؤلفون: | Chang W; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Altman MD; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Lesburg CA; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Perera SA; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Piesvaux JA; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Schroeder GK; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Wyss DF; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Cemerski S; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Chen Y; Merck & Co., Inc., Boston, Massachusetts 02115, United States., DiNunzio E; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Haidle AM; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Ho T; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Kariv I; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Knemeyer I; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Kopinja JE; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Lacey BM; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Laskey J; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Lim J; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Long BJ; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Ma Y; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Maddess ML; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Pan BS; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Presland JP; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Spooner E; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Steinhuebel D; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Truong Q; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Zhang Z; Pharmaron Beijing Co. Ltd., Beijing 100176, P. R. China., Fu J; Pharmaron Beijing Co. Ltd., Beijing 100176, P. R. China., Addona GH; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Northrup AB; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Parmee E; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Tata JR; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Bennett DJ; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Cumming JN; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Siu T; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Trotter BW; Merck & Co., Inc., Boston, Massachusetts 02115, United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2022 Apr 14; Vol. 65 (7), pp. 5675-5689. Date of Electronic Publication: 2022 Mar 25. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S. |
| 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: | Membrane Proteins* , Neoplasms*/drug therapy, Animals ; Cytokines ; Humans ; Immunotherapy/methods ; Interferons ; Mice |
| مستخلص: | Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed and synthesized to access a previously unexplored chemical space. The assessment of biochemical affinity and cellular potency, along with computational, structural, and biophysical characterization, was applied to influence the design and optimization of novel STING agonists, resulting in the discovery of MK-1454 as a molecule with appropriate properties for clinical development. When administered intratumorally to immune-competent mice-bearing syngeneic tumors, MK-1454 exhibited robust tumor cytokine upregulation and effective antitumor activity. Tumor shrinkage in mouse models that are intrinsically resistant to single-agent therapy was further enhanced when treating the animals with MK-1454 in combination with a fully murinized antimouse PD-1 antibody, mDX400. These data support the development of STING agonists in combination with pembrolizumab (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 therapy. |
| المشرفين على المادة: | 0 (Cytokines) 0 (Membrane Proteins) 9008-11-1 (Interferons) |
| تواريخ الأحداث: | Date Created: 20220325 Date Completed: 20220415 Latest Revision: 20220508 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1021/acs.jmedchem.1c02197 |
| PMID: | 35332774 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.1c02197 |