Anti-leukaemic Activity of the TYK2 selective inhibitor NDI-031301 in T-cell Acute Lymphoblastic Leukaemia

Details

• Alternative Title:
  Br J Haematol
• Personal Author:
  Akahane, Koshi ; Li, Zhaodong ; Etchin, Julia ; Berezovskaya, Alla ; Gjini, Evisa ; Masse, Craig E. ; Miao, Wenyan ; Rocnik, Jennifer ; Kapeller, Rosana ; Greenwood, Jeremy R. ; Tiv, Hong ; Sanda, Takaomi ; Weinstock, David M. ; Look, A. Thomas
• Description:
  Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI-031301 treatment and was responsible for NDI-031301-induced T-ALL cell death, as pharmacological inhibition of p38 MAPK partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI-031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT-K1 T-ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T-ALL.
• Subjects:
  Animals Cell Line, Tumor Female Humans Mice Mice, Inbred NOD Mice, SCID Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Protein Kinase Inhibitors TYK2 Kinase Xenograft Model Antitumor Assays

  More +
• Source:
  Br J Haematol. 177(2):271-282.
• Pubmed ID:
  28295194
• Pubmed Central ID:
  PMC5384871
• Document Type:
  Journal Article
• Funding:
  R01 CA176746/CA/NCI NIH HHS/United States ; R35 CA210064/CA/NCI NIH HHS/United States ; U48 DP005014/DP/NCCDPHP CDC HHS/United States
• Volume:
  177
• Issue:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:8fae77e24c4dfb9ed9e88a035dded04744175a06f677199ad52fffef519d9e89
• Download URL:
  https://stacks.cdc.gov/view/cdc/53009/cdc_53009_DS1.pdf
• File Type:
  [PDF - 1.29 MB ]