Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease

Abstract

Summary Tumor necrosis factor α (TNFα) has both positive and negative roles in human disease. In certain cancers, TNFα is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNFα antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNFα-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNFα stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated TAK1 that binds within the ATP binding pocket, yet is non-competitive, and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNFα-induced cell death, with general implications for cancer and autoimmune disease treatment.

Preclinical validation of therapeutic targets predicted by tensor factorization on heterogeneous graphs

“…The difference between SB202190 and DMSO provided the signal-to-background ratio of our experiment. SB202190 was chosen as a positive control, as it has been shown to significantly control fibroblast-like synoviocyte activation 87 and provided a strong assay window.…”

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

“…At present, it is believed that there are additional transcription‐independent early cell death checkpoints regulated by phosphorylation of RIPK1 . Consistent with this possibility, genetic deletion or pharmacological inhibition of TAK1 and IKKα/β resulted in further sensitization of cell death by activating RIPK1, independently of NF‐κB activation . Subsequent biochemical analyses revealed that RIPK1 phosphorylation on Ser 321 or Ser 25 by TAK1 or IKKα/β in complex‐I prevented the RIPK1‐mediated assembly of the complex‐II/necrosome and then inhibited apoptosis/necroptosis in an NF‐κB‐independent manner .…”

“…16,17 Consistent with this possibility, genetic deletion or pharmacological inhibition of TAK1 and IKKα/β resulted in further sensitization of cell death by activating RIPK1, independently of NF-κB activation. 18,19 Subsequent biochemical analyses revealed that RIPK1 phosphorylation on Ser 321 or Ser 25 by TAK1 or IKKα/β in complex-I prevented the RIPK1-mediated assembly of the complex-II/necrosome and then inhibited apoptosis/necroptosis in an NF-κBindependent manner. 20,21 Furthermore, it has been proposed that MAPK-activated protein kinase 2 (MK2) also induces RIPK1 phosphorylation in complex-I and protects against complex-II-mediated cell death.…”

Genetic and pharmacological validation of TAK1 inhibition in macrophages as a therapeutic strategy to effectively inhibit TNF secretion

“…Previous studies in cancer cells show TAK1 inhibitors reduced phosphorylation of many downstream signaling molecules including p-IKK p-p-38, and p-c-Jun following TNF stimulation. Takinib, a novel TAK1 inhibitor, has been shown to potently inhibit TAK1 (IC50 of~9 nM) in vitro kinase assays and, unlike many other TAK1 kinase inhibitors, Takinib has an exquisite selectivity towards TAK1 over all other protein kinases in the human kinome 22 . In this study we show Takinib potently reduces pro-inflammatory phenotypes and functional responses of the TLR4 receptor in response to LPS challenge.…”