title: 4-Amino-2-arylamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-(8H)-ones as BCR kinase inhibitors for B lymphoid malignancies.
abstract: A new family of 4-aminopyrido[2,3-d]pyrimidines active against non-Hodgkin's lymphomas (NHLs) is described. Among these compounds, 19 inhibits the most upstream tyrosine kinases in the B cell receptor (BCR) signaling pathway which are involved in the mature B cell neoplasms. Thus, 19 showed antiproliferative activity at 24 h and 48 h against a panel of 20 NHLs cell lines with GI50 ranging from 1.3 to 6.9 μM at 24 h, and 1.4-7.2 μM at 48 h, being this effect related to a significant (20-90%) inhibition of the phosphorylation of the BCR-related kinases Btk, Syk, and Lyn. Most importantly, 19 was able to induce a 63% reduction in Rec-1 cell proliferation, which was significantly greater than the 31% and 3% blockade of proliferation observed after cell treatment with R406, a Syk inhibitor, and ibrutinib, a Btk inhibitor, respectively. The computational blind docking and ligand binding within the pockets of Btk, Syk and Lyn kinases showed that compound 19 presents the same kind of interactions of described cocrystallized inhibitors.
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: raimonpc@gmail.com.
authors.forename: Raimon
authors.initials: R
authors.lastname: Puig de la Bellacasa
authors.affiliation: Institut d'Investigacions Mèdiques August Pi i Sunyer (IDIBAPS), Rosselló, 149-153, E-08036 Barcelona, Spain. Electronic address: groue@clinic.ub.es.
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.affiliation: Institut d'Investigacions Mèdiques August Pi i Sunyer (IDIBAPS), Rosselló, 149-153, E-08036 Barcelona, Spain. Electronic address: PBALSAS@clinic.ub.es.
authors.forename: Patricia
authors.initials: P
authors.lastname: Balsas
authors.affiliation: Institut d'Investigacions Mèdiques August Pi i Sunyer (IDIBAPS), Rosselló, 149-153, E-08036 Barcelona, Spain. Electronic address: PPEREZ@clinic.ub.es.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pérez-Galán
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: jordi.teixido@iqs.url.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Teixidó
authors.affiliation: Institut d'Investigacions Mèdiques August Pi i Sunyer (IDIBAPS), Rosselló, 149-153, E-08036 Barcelona, Spain. Electronic address: dcolomer@clinic.cat.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: j.i.borrell@iqs.url.edu.
authors.forename: José I
authors.initials: JI
authors.lastname: Borrell
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011744:Pyrimidinones; D020794:Receptor Protein-Tyrosine Kinases
keywords: 7-oxopyrido[2,3-d]pyrimidines; B-cell receptor; Kinases; Non-Hodgkin's lymphomas; Small molecule inhibitor