title: Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors.
abstract: Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chemical optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFα. Pharmacological profiling in vivo revealed a high metabolism of these compounds in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compounds both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases.
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Ralf
authors: R
authors: Glatthar
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Aleksandar
authors: A
authors: Stojanovic
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Thomas
authors: T
authors: Troxler
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Henri
authors: H
authors: Mattes
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Henrik
authors: H
authors: Möbitz
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Rene
authors: R
authors: Beerli
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Joachim
authors: J
authors: Blanz
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Ernst
authors: E
authors: Gassmann
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Peter
authors: P
authors: Drückes
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Gabriele
authors: G
authors: Fendrich
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Sascha
authors: S
authors: Gutmann
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Georg
authors: G
authors: Martiny-Baron
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Fiona
authors: F
authors: Spence
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Jeff
authors: J
authors: Hornfeld
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: John Edmonson
authors: JE
authors: Peel
authors: Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors: Helmut
authors: H
authors: Sparrer
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human