Recent Advances in the Structure-Based and Ligand-Based Design of IKKβ Inhibitors as Anti-inflammation and Anti-cancer Agents

Abstract

NF-κB is a significant transcription factor that regulates the expression of various pro-survival genes. IKK is a crucial protein kinase that activates NF-κB translocating from cytoplasm to nucleus for DNA binding. It is composed of three subunits, IKKα, IKKβ, IKKγ (NEMO), where IKKα and IKKβ are catalytic subunits, and IKKγ is the regulatory subunit. Many diseases, such as Hodgkin's disease, Hepatitis-associated hepatocellular carcinoma, colorectal cancer, prostate cancer, rheumatoid arthritis and inflammatory bowel disease, are related to IKK and NF-κB. So far, various IKK inhibitors targeting the ATP binding site have been identified through high throughput screening, rational design or in silico methods, however, only three of them (CHS-828, EB-1627 and IMD-1041) have been under clinical studies, indicating the strategy for the design of IKK inhibitors need to be reinspected. Besides ATP-competitive inhibitors, several other inhibitors have also been disclosed recently, which provide novel concepts to the discovery of IKK inhibitors. In this review, we focus on two parts: 1) the chemotypes and binding patterns of the traditional ATP-competitive IKK inhibitors; 2) novel strategies for the identification of non-ATP-competitive IKK inhibitors as NF-κB modulators. Through these discussions we hope to present inspirations for the development of new IKK inhibitors.

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

“…NF-κB is found in almost all cell types and can be activated by proinflammatory cytokines and endotoxins, and then translocated to the nucleus to regulate inducible gene expression [50,51]. Constitutive NF-κB activation not only correlates closely with inflammatory responses, but also is generally associated with cancer proliferation, survival and progression of HCC [52,53]. In this study, Ang II-induced NF-κB expression and activation was significantly suppressed by the PKC inhibitor CH, providing the proof that PKC is a critical component for Ang II-dependent NF-κB activation in HCC cells.…”

Estrogen receptor β suppresses inflammation and the progression of prostate cancer

“…In this context, nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), a master transcription factor, has been reported as the main mediator of proinflammatory processes in the pathogenesis of prostate cancer (8). During the progression of prostate cancer, NF-κB promotes tumor invasion, metastasis, cell survival and chemoresistance (9). Constitutive activation of NF-κB has been demonstrated in primary prostate cancer, and is associated with castration-resistant phenotypes and the loss of androgen receptor function (10).…”

Design, synthesis, and biological evaluation of novel <strong>EF24 </strong>and <strong>EF31 </strong>analogs as potential I&kappa;B kinase &beta; inhibitors for the treatment of pancreatic cancer

“…The lead compounds EF31 , EF24 , and CUR are used for comparison. 1.92 a and 1.9 a were the IC 50 values of EF31 and EF24 , respectively, against IKKβ 31,32. All data are presented as the mean value of three to five independent tests.…”

“…28–30 Nonetheless, no small-molecule IKKβ inhibitor has been approved for clinical applications so far 31. Part of the reason for these inhibitors possessing excellent enzymatic inhibitory activity but failing in the preclinical trials is their poor metabolism and severe toxicity to normal cells.…”