8SE5

NKG2D complexed with inhibitor 14

Summary for 8SE5

• Entry DOI: 10.2210/pdb8se5/pdb
• Descriptor: NKG2-D type II integral membrane protein, TRIETHYLENE GLYCOL, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• Functional Keywords: nkg2d, immune system, immunosuppressant-inhibitor complex, immune system-inhibitor complex, immune system/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 31030.98

Authors

Thompson, A.A.,Grant, J.C.,Karpowich, N.K.,Sharma, S. (deposition date: 2023-04-08, release date: 2023-10-11, Last modification date: 2024-11-20)

Primary citation

Wang, J.,Nakafuku, K.M.,Ziff, J.,Gelin, C.F.,Gholami, H.,Thompson, A.A.,Karpowich, N.K.,Limon, L.,Coate, H.R.,Damm-Ganamet, K.L.,Shih, A.Y.,Grant, J.C.,Cote, M.,Mak, P.A.,Pascual, H.A.,Rives, M.L.,Edwards, J.P.,Venable, J.D.,Venkatesan, H.,Shi, Z.,Allen, S.J.,Sharma, S.,Kung, P.P.,Shireman, B.T.
Development of small molecule inhibitors of natural killer group 2D receptor (NKG2D).
Bioorg.Med.Chem.Lett., 96:129492-129492, 2023

PubMed Abstract: 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.

PubMed: 37778428
DOI: 10.1016/j.bmcl.2023.129492

Experimental method

X-RAY DIFFRACTION (1.43 Å)