Design of pyrido[2,3-d]pyrimidin-7-one inhibitors of receptor interacting protein kinase-2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling

Receptor Interacting Ser/Thr-Protein Kinase 2 as a New Therapeutic Target

“…Recently, several type II RIPK2 inhibitors have been discovered. ,,− During their structural study, Charnley et al identified two type II inhibitors in addition to the type I inhibitor 12 previously described: a biaryl urea, inhibitor 24 , and a biphenyl sulfonamide, inhibitor 25 (Figure ). Inhibitor 24 binds to a DFG-out conformation of RIPK2, with its tert -butyl isoxazole in an allosteric hydrophobic pocket present only in the DFG-out conformation (Figure ; [PDB: 5AR7]), while inhibitor 25 binds to a helix αC-out conformation of RIPK2 (Figure ; [PDB: 5AR8]).…”

“…More recently, the same group developed a new class of RIPK2 inhibitors using a different strategy. ,− They considered two scaffolds from previously identified activin receptor-like kinase 2 (ALK2) inhibitors during one of their research studies, which exhibited off-target effects on RIPK2. They identified the 3,5-diphenyl-2-aminopyridine scaffold with CSLP37 ( 28 ), ,, and the pyrido­[2,3- d ]­pyrimidin-7-one scaffold with UH15-15 ( 29 ) (Figure ).…”

“…They identified the 3,5-diphenyl-2-aminopyridine scaffold with CSLP37 ( 28 ), ,, and the pyrido­[2,3- d ]­pyrimidin-7-one scaffold with UH15-15 ( 29 ) (Figure ). CSLP37 ( 28 ) and UH15-15 ( 29 ) showed potent inhibition of RIPK2 in a type II manner and NOD2 cell signaling inhibition. Selectivity toward RIPK2 versus ALK2 was achieved with the methoxy group in the para position of the sulfonamide on CSLP37 ( 28 ), and with the addition of a sulfoxide for UH15-15 ( 29 ).…”

“…Type II RIPK2 inhibitors from diverse research teams with their inhibitory activity of RIPK2 autophosphorylation. ,,− IC 50 = half-maximal inhibitory concentration.…”

“…As type II are larger compounds, they can also bind other amino acids such as Asp 151 (CSLP37 ( 28 )), Lys 69 (CSR35 ( 27 )), and Phe 165 (inhibitors 24 and 25 ), which makes it more difficult to delineate a common structure and strong SAR for these inhibitors. Their binding mode also differs depending on the compounds: inhibitors 24 , 25 , 26 , and CSR35 ( 27 ) interact with a hydrophobic pocket that is only visible in the DFG-out conformation while CSLP37 ( 28 ) and UH15-15 ( 29 ) induce this inactive state by binding to another hydrophobic pocket close to Lys 47 . ,,− Type II inhibitor interaction with Ser 25 does not seem as significant for selectivity as type I inhibitors. If inhibitors 25 and 26 are taken as an example, the nonselective inhibitor 25 binds Ser 25 while the selective inhibitor 26 does not.…”