title: Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators.
abstract: Unique chemical methodology enables the synthesis of innovative and diverse scaffolds and chemotypes and allows access to previously unexplored "chemical space." Compound collections based on such new synthetic methods can provide small-molecule probes of proteins and/or pathways whose functions are not fully understood. We describe the identification, characterization, and evolution of two such probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified a compound, MARPIN (ATM and ATR pathway inhibitor) that sensitizes p53-deficient cells to DNA-damaging agents. Modification of the small molecule and generation of an immobilized probe were used to selectively bind putative protein target(s) responsible for the observed activity. The second example describes a focused library approach that relied on tandem multicomponent reaction methodologies to afford a series of modulators of the heat shock protein 70 (Hsp70) molecular chaperone. The synthesis of libraries based on the structure of MAL3-101 generated a collection of chemotypes, each modulating Hsp70 function, but exhibiting divergent pharmacological activities. For example, probes that compromise the replication of a disease-associated polyomavirus were identified. These projects highlight the importance of chemical methodology development as a source of small-molecule probes and as a drug discovery starting point.
authors.affiliation: University of Pittsburgh Center for Chemical Methodologies and Library Design, Chevron Science Center, Parkman Avenue, Pittsburgh, PA 15260, USA. huryn@pitt.edu
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
authors.forename: Kay M
authors.initials: KM
authors.lastname: Brummond
authors.forename: Peter G
authors.initials: PG
authors.lastname: Chambers
authors.forename: Benjamin
authors.initials: B
authors.lastname: Eyer
authors.forename: Alex W
authors.initials: AW
authors.lastname: Ireland
authors.forename: Masaoki
authors.initials: M
authors.lastname: Kawasumi
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Laporte
authors.forename: Kayla
authors.initials: K
authors.lastname: Lloyd
authors.forename: Baptiste
authors.initials: B
authors.lastname: Manteau
authors.forename: Paul
authors.initials: P
authors.lastname: Nghiem
authors.forename: Bettina
authors.initials: B
authors.lastname: Quade
authors.forename: Sandlin P
authors.initials: SP
authors.lastname: Seguin
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D015195:Drug Design; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011120:Polyomavirus / Q000502:physiology; D027601:Polyomavirus Infections / Q000188:drug therapy / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D015335:Molecular Probes; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases