دورية أكاديمية
أعرض في EDS

Development of small molecule inhibitors of natural killer group 2D receptor (NKG2D).

التفاصيل البيبلوغرافية
العنوان: Development of small molecule inhibitors of natural killer group 2D receptor (NKG2D).
المؤلفون: Wang J; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States. Electronic address: jwang301@its.jnj.com., Nakafuku KM; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States. Electronic address: knakafuk@its.jnj.com., Ziff J; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Gelin CF; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Gholami H; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Thompson AA; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Karpowich NK; Janssen Research & Development L.L.C., 1400 McKean Rd., Spring House, PA 19477, United States., Limon L; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Coate HR; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Damm-Ganamet KL; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Shih AY; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Grant JC; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Côte M; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Mak PA; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Pascual HA; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Rives ML; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Edwards JP; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Venable JD; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Venkatesan H; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Shi Z; Janssen Research & Development L.L.C., 1400 McKean Rd., Spring House, PA 19477, United States., Allen SJ; Janssen Research & Development L.L.C., 1400 McKean Rd., Spring House, PA 19477, United States., Sharma S; Janssen Research & Development L.L.C., 1400 McKean Rd., Spring House, PA 19477, United States., Kung PP; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States., Shireman BT; Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States.
المصدر: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2023 Nov 15; Vol. 96, pp. 129492. Date of Electronic Publication: 2023 Sep 29.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
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: NK Cell Lectin-Like Receptor Subfamily K*/metabolism , Carrier Proteins*/metabolism, Humans ; Histocompatibility Antigens Class I/metabolism ; Protein Binding ; Killer Cells, Natural/metabolism ; Ligands
مستخلص: Natural killer group 2D (NKG2D) is a homodimeric activating immunoreceptor whose function is to detect and eliminate compromised cells upon binding to the NKG2D ligands (NKG2DL) major histocompatibility complex (MHC) molecules class I-related chain A (MICA) and B (MICB) and UL16 binding proteins (ULBP1-6). While typically present at low levels in healthy cells and tissue, NKG2DL expression can be induced by viral infection, cellular stress or transformation. Aberrant activity along the NKG2D/NKG2DL axis has been associated with autoimmune diseases due to the increased expression of NKG2D ligands in human disease tissue, making NKG2D inhibitors an attractive target for immunomodulation. Herein we describe the discovery and optimization of small molecule PPI (protein-protein interaction) inhibitors of NKG2D/NKG2DL. Rapid SAR was guided by structure-based drug design and accomplished by iterative singleton and parallel medicinal chemistry synthesis. These efforts resulted in the identification of several potent analogs (14, 21, 30, 45) with functional activity and improved LLE.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
فهرسة مساهمة: Keywords: Cryptic pocket; Immunoreceptors; NKG2D; Protein–protein interactions; Structure-based drug design
المشرفين على المادة: 0 (NK Cell Lectin-Like Receptor Subfamily K)
0 (Carrier Proteins)
0 (Histocompatibility Antigens Class I)
0 (Ligands)
تواريخ الأحداث: Date Created: 20231001 Date Completed: 20231127 Latest Revision: 20240104
رمز التحديث: 20240105
DOI: 10.1016/j.bmcl.2023.129492
PMID: 37778428
قاعدة البيانات: MEDLINE
الوصف
تدمد:1464-3405
DOI:10.1016/j.bmcl.2023.129492