title: Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP.
abstract: Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis and pro-survival signaling pathways whose deregulation is often associated with tumor genesis and tumor growth. IAPs have been proposed as targets for anticancer therapy, and a number of peptidomimetic IAP antagonists have entered clinical trials. Using our fragment-based screening approach, we identified nonpeptidic fragments binding with millimolar affinities to both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure-based hit optimization together with an analysis of protein-ligand electrostatic potential complementarity allowed us to significantly increase binding affinity of the starting hits. Subsequent optimization gave a potent nonalanine IAP antagonist structurally distinct from all IAP antagonists previously reported. The lead compound had activity in cell-based assays and in a mouse xenograft efficacy model and represents a highly promising start point for further optimization.
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Gianni
authors.initials: G
authors.lastname: Chessari
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Ildiko M
authors.initials: IM
authors.lastname: Buck
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: James E H
authors.initials: JE
authors.lastname: Day
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Day
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Aman
authors.initials: A
authors.lastname: Iqbal
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lewis
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Martins
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Darcey
authors.initials: D
authors.lastname: Miller
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Reader
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Rees
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Sharna J
authors.initials: SJ
authors.lastname: Rich
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Tamanini
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: Vitorino
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: George A
authors.initials: GA
authors.lastname: Ward
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Williams
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Glyn
authors.initials: G
authors.lastname: Williams
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Nicola E
authors.initials: NE
authors.lastname: Wilsher
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Alison J-A
authors.initials: AJ
authors.lastname: Woolford
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D015195:Drug Design; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D010446:Peptide Fragments; D010879:Piperazines; D051636:X-Linked Inhibitor of Apoptosis Protein