Interleukin-1 receptor associated kinase inhibitors: potential therapeutic agents for inflammatory- and immune-related disorders.
The various cells of innate immune system quickly counter-attack invading pathogens, and mount up "first line" defense through their trans-membrane receptors including Toll-like receptors (TLRs) and interleukin receptors (IL-Rs) that result in the secretion of pro-inflammatory cytokines. Albeit such inflammatory responses are beneficial in pathological conditions, their overstimulation may cause severe inflammatory damage; thus, make this defense system a "double edged sword". IRAK-4 has been evaluated as an indispensable element of IL-Rs and TLR pathways that can regulate the abnormal levels of cytokines, and therefore could be employed to manage immune- and inflammation-related disorders. Historically, the identification of selective and potent inhibitors has been challenging; thus, a limited number of small molecule IRAK-4 inhibitors are available in literature. Recently, IRAK-4 achieved great attention, when Ligand® pharmaceutical and Nimbus Discovery® reported the beneficial potentials of IRAK-4 inhibitors in the pre-clinical evaluation for various inflammatory- and immune-related disorders, but not limited to, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, gout, asthma and cancer.
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Malkeet Singh
MS
Bahia
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Maninder
M
Kaur
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Pragati
P
Silakari
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India. Electronic address: omsilakari@rediffmail.com.
Om
O
Silakari
D000577:Amides / Q000737:chemistry / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism
D000577:Amides; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D051193:Toll-Like Receptors; C000601850:thieno(2,3-d)pyrimidine; C031000:benzimidazole; D053592:Interleukin-1 Receptor-Associated Kinases; C001439:imidazo(1,2-a)pyridine
Inflammation; Interleukin-1 receptor associated kinase-4 (IRAK-4); MyD88-dependent and independent pathways; TLR/IL-1 receptor (TIR) superfamily; Toll-like receptors