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

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

  • Bioorg Med Chem Lett. 2023 Sep 29:96:129492. doi: 10.1016/j.bmcl.2023.129492.
Jocelyn Wang 1,  Kohki M Nakafuku 2,  Jeannie Ziff 3,  Christine F Gelin 3,  Hadi Gholami 3,  Aaron A Thompson 3,  Nathan K Karpowich 4,  Luis Limon 3,  Heather R Coate 3,  Kelly L Damm-Ganamet 3,  Amy Y Shih 3,  Joanna C Grant 3,  Marjorie Côte 3,  Puiying A Mak 3,  Heather A Pascual 3,  Marie-Laure Rives 3,  James P Edwards 3,  Jennifer D Venable 3,  Hariharan Venkatesan 3,  Zhicai Shi 4,  Samantha J Allen 4,  Sujata Sharma 4,  Pei-Pei Kung 3,  Brock T Shireman 3
Affiliations

Affiliations

  • 1 Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States. Electronic address: [email protected].
  • 2 Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States. Electronic address: [email protected].
  • 3 Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, United States.
  • 4 Janssen Research & Development L.L.C., 1400 McKean Rd., Spring House, PA 19477, United States.
PMID: 37778428 DOI: 10.1016/j.bmcl.2023.129492
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.

Keywords

Cryptic pocket; Immunoreceptors; NKG2D; Protein–protein interactions; Structure-based drug design.

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