Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader

• DOI: 10.1021/acschembio.9b00505
• Publication Date: 2019-08-28T19:54:45Z
• Authors: Hannah Tovell; Andrea Testa; Houjiang Zhou; Natalia Shpiro; Claire Crafter; Alessio Ciulli; Dario R. Alessi
• Keywords: /dk/atira/pure/subjectarea/asjc/1300/1313; 0301 basic medicine; Indazoles; Ubiquitin-Protein Ligases; 610; Mechanistic Target of Rapamycin Complex 1; Protein Serine-Threonine Kinases; 03 medical and health sciences; Cell Line, Tumor; name=Molecular Medicine; Humans; Pyrroles; Protein Kinase Inhibitors; Cell Proliferation; /dk/atira/pure/subjectarea/asjc/1300/1303; Sulfonamides; name=Biochemistry; Dipeptides; 3. Good health; Pyrimidines; Drug Design; Proteolysis; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction

SGK3 is a PX domain containing protein kinase activated at endosomes downstream of class 1 and 3 PI3K family members by growth factors oncogenic mutations. plays key role in mediating resistance breast cancer cells to or Akt inhibitors, substituting for the loss activity restoring proliferative pathways such as mTORC1 signaling. It therefore critical develop tools potently target obstruct its inhibitor resistance. Here, we describe development SGK3-PROTAC1, PROTAC conjugate 308-R SGK with VH032 VHL binding ligand, targeting degradation. SGK3-PROTAC1 (0.3 μM) induced 50% degradation endogenous within 2 h, maximal 80% observed 8 accompanied phosphorylation NDRG1, an substrate. did not degrade closely related SGK1 SGK2 isoforms that are nevertheless engaged inhibited 308-R. Proteomic analysis revealed was only cellular whose levels were significantly reduced following treatment SGK3-PROTAC1. Low doses (0.1–0.3 restored sensitivity dependent ZR-75-1 CAMA-1 (AZD5363) (GDC0941) whereas cis epimer analogue incapable E3 ligase had no impact. suppressed proliferation cell lines treated more effectively than could be achieved conventional isoform (14H). This work underscores benefit approach signaling greater efficacy selectivity can inhibitors. will important reagent explore roles pathway.