title: The generation of purinome-targeted libraries as a means to diversify ATP-mimetic chemical classes for lead finding.
abstract: The generation of novel chemotypes in support of our oncology research projects expanded in recent years from a canonical design of kinase-targeted compound libraries to a broader interpretation of purinome-targeted libraries (PTL) addressing the specificity of cancer relevant targets such as kinases and ATPases. Successful screening of structurally diverse ATP-binding targets requires compound libraries covering multiple design elements, which may include phosphate surrogate moieties in ATPase inhibitors or far reaching lipophilic residues stabilizing inactive kinase conformations. Here, we exemplify the design and preparation of drug-like combinatorial libraries and report significantly enhanced screening performance on purinomic targets. We compared overall hit rates of PTL with a simultaneously tested unbiased collection of 200,000 compounds and found consistent superiority of the targeted libraries in all cases. We also analyzed the performance of the largest targeted libraries in comparison with each other and often found striking differences in how a specific target responds to various chemotypes and to whole collections.
authors.affiliation: Oncology Research, Nerviano Medical Sciences, Viale Pasteur 10, 20014, Nerviano, Italy. eduard.felder@nervianoms.com
authors.forename: Eduard R
authors.initials: ER
authors.lastname: Felder
authors.forename: Alessandra
authors.initials: A
authors.lastname: Badari
authors.forename: Teresa
authors.initials: T
authors.lastname: Disingrini
authors.forename: Sergio
authors.initials: S
authors.lastname: Mantegani
authors.forename: Christian
authors.initials: C
authors.lastname: Orrenius
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.forename: Barbara
authors.initials: B
authors.lastname: Salom
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D019992:Databases as Topic; D015195:Drug Design; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry; D012015:Reference Standards; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D011494:Protein Kinases