The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

Abstract

NF-κB transcription factors are major drivers of tumor initiation and progression. NF-κB signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, metabolic reprogramming, tissue invasion, angiogenesis, and metastasis. As such, the NF-κB pathway is an attractive therapeutic target in a broad range of human cancers, as well as in numerous non-malignant diseases. Currently, however, there is no clinically useful NF-κB inhibitor to treat oncological patients, owing to the preclusive, on-target toxicities of systemic NF-κB blockade. In this review, we discuss the principal and most promising strategies being developed to circumvent the inherent limitations of conventional IκB kinase (IKK)/NF-κB-targeting drugs, focusing on new molecules that target upstream regulators or downstream effectors of oncogenic NF-κB signaling, as well as agents targeting individual NF-κB subunits.

Design of Sonosensitizers Integrated with Resveratrol Motif for Synergetic Sonodynamic Therapy and Nuclear Factor Kappa B Transcription Suppression of Breast Cancer

“…The residue was purified by column chromatography on silica gel chromatography to yield the desirable product. [1,2,5]thiadiazol-4-yl)phenyl)aniline (TR1). Red solid, 35% yield, HPLC Purity is >95%; 1 H NMR (600 MHz, Chloroform-d) δ 8.12 (dd, J = 3.7, 1.1 Hz, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.45 (dd, J = 5.1, 1.1 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.24−7.20 (m, 3H), 7.13 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.03 (s, 1H), 6.96 (d, J = 16.2 Hz, 1H), 6.66 (d, J = 2.2 Hz, 2H), 6.39 (t, J = 2.3 Hz, 1H), 3.83 (s, 6H).…”

“…Many pathogens, growth factors, cytokines, and carcinogens that induce the activation of NF-κB have been implicated in the promotion and pathogenesis of cancer . There is now considerable evidence that sustained or constitutive activation of NF-κB is prevalent in a variety of carcinomas, including breast, colon, pancreatic, ovarian, melanoma, and lymphoma cancers. − Although the activation mechanisms are incompletely understood, aberrant NF-κB signaling has been found to enhance cancer cell proliferation, metastasis, angiogenesis, and chemoresistance in most primary forms of human cancer . Therefore, immense attention has been paid to developing drugs that target the NF-κB signaling pathways.…”

Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

“…AP-1 is a heterodimer transcription factor that regulates the expression of key inflammatory-associated genes in response to a variety of stimuli, including cytokines, and it consists of members belonging to the basic leucine-zipper (bZIP) proteins, mainly of the Jun and the Fos families [ 40 , 41 ]. In mammalian cells, NF-κB family comprises five members of DNA-binding subunits which are: p65 (RelA), RelB, c-Rel, p105/p50 (NF-κB1) and p100/p52 (NF-κB2) [ 42 ]. These transcription factors mediate signaling from the cell surface to regulate key genes involved in inflammation, cell division and immunity [ 42 ].…”

“…In mammalian cells, NF-κB family comprises five members of DNA-binding subunits which are: p65 (RelA), RelB, c-Rel, p105/p50 (NF-κB1) and p100/p52 (NF-κB2) [ 42 ]. These transcription factors mediate signaling from the cell surface to regulate key genes involved in inflammation, cell division and immunity [ 42 ]. Unlike other IRAK family members, IRAK3 negatively regulates the IL1R/TLRs signaling pathway.…”

NF-κB: Governing Macrophages in Cancer

“…The NF-κB family is composed of five structurally related DNA-binding subunits, consisting of the homo-and heterodimers of p50, p52, c-Rel, RelA (p65), RelB and c-Rel, which control transcription of target genes by binding specific DNA elements, called κB enhancers [40][41][42]. In resting cells, the NF-κB complexes are retained into the cytoplasm, bound to the inhibitory proteins of IκB family [43].…”