title: Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity.
abstract: Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 microM in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 microM in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (>80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.
authors.affiliation: Department of Chemistry, Biogen Idec, Inc., 5200 Research Place, San Diego, CA 92122, USA. srinivasrao.kasibhatla@biogenidec.com
authors.forename: Srinivas R
authors.initials: SR
authors.lastname: Kasibhatla
authors.forename: Kevin
authors.initials: K
authors.lastname: Hong
authors.forename: Marco A
authors.initials: MA
authors.lastname: Biamonte
authors.forename: David J
authors.initials: DJ
authors.lastname: Busch
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Karjian
authors.forename: John L
authors.initials: JL
authors.lastname: Sensintaffar
authors.forename: Adeela
authors.initials: A
authors.lastname: Kamal
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Lough
authors.forename: John
authors.initials: J
authors.lastname: Brekken
authors.forename: Karen
authors.initials: K
authors.lastname: Lundgren
authors.forename: Roy
authors.initials: R
authors.lastname: Grecko
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Timony
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Ran
authors.forename: Robert
authors.initials: R
authors.lastname: Mansfield
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Fritz
authors.forename: Edgar
authors.initials: E
authors.lastname: Ulm
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Burrows
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Boehm
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000225:Adenine; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011687:Purines; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; C521961:2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine; C521963:6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine; C521962:6-chloro-9-(5-methoxy-4,6-dimethylpyridin-3-ylmethyl)-9H-purin-2-ylamine