title: GDC-0449-a potent inhibitor of the hedgehog pathway.
abstract: SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.
authors.affiliation: Genentech, Small Molecule Drug Discovery 1 DNA Way, South San Francisco, CA 94080, United States. kir@gene.com
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Robarge
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Brunton
authors.forename: Georgette M
authors.initials: GM
authors.lastname: Castanedo
authors.forename: Yong
authors.initials: Y
authors.lastname: Cui
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dina
authors.forename: Richard
authors.initials: R
authors.lastname: Goldsmith
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Oivin
authors.initials: O
authors.lastname: Guichert
authors.forename: Janet L
authors.initials: JL
authors.lastname: Gunzner
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.forename: Cyrus
authors.initials: C
authors.lastname: Khojasteh
authors.forename: Michael F T
authors.initials: MF
authors.lastname: Koehler
authors.forename: Karen
authors.initials: K
authors.lastname: Kotkow
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Lalonde
authors.forename: Kevin
authors.initials: K
authors.lastname: Lau
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.forename: Derek
authors.initials: D
authors.lastname: Marshall
authors.forename: James C
authors.initials: JC
authors.lastname: Marsters
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Murray
authors.forename: Changgeng
authors.initials: C
authors.lastname: Qian
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Mark S
authors.initials: MS
authors.lastname: Stanley
authors.forename: John H A
authors.initials: JH
authors.lastname: Stibbard
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
authors.forename: Savita
authors.initials: S
authors.lastname: Ubhayaker
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.forename: Minli
authors.initials: M
authors.lastname: Xie
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D002280:Basal Cell Carcinoma / Q000188:drug therapy; D002460:Cell Line; D002528:Cerebellar Neoplasms / Q000188:drug therapy; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D000813:Anilides; D001562:Benzimidazoles; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines