title: Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.
abstract: WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SW7 3RP, U.K.
authors: Aurélie
authors: A
authors: Mallinger
authors: Simon
authors: S
authors: Crumpler
authors: Mark
authors: M
authors: Pichowicz
authors: Dennis
authors: D
authors: Waalboer
authors: Mark
authors: M
authors: Stubbs
authors: Olajumoke
authors: O
authors: Adeniji-Popoola
authors: Bozena
authors: B
authors: Wood
authors: Elizabeth
authors: E
authors: Smith
authors: Ching
authors: C
authors: Thai
authors: Alan T
authors: AT
authors: Henley
authors: Katrin
authors: K
authors: Georgi
authors: William
authors: W
authors: Court
authors: Steve
authors: S
authors: Hobbs
authors: Gary
authors: G
authors: Box
authors: Maria-Jesus
authors: MJ
authors: Ortiz-Ruiz
authors: Melanie
authors: M
authors: Valenti
authors: Alexis
authors: A
authors: De Haven Brandon
authors: Robert
authors: R
authors: TePoele
authors: Birgitta
authors: B
authors: Leuthner
authors: Paul
authors: P
authors: Workman
authors: Wynne
authors: W
authors: Aherne
authors: Oliver
authors: O
authors: Poeschke
authors: Trevor
authors: T
authors: Dale
authors: Dirk
authors: D
authors: Wienke
authors: Christina
authors: C
authors: Esdar
authors: Felix
authors: F
authors: Rohdich
authors: Florence
authors: F
authors: Raynaud
authors: Paul A
authors: PA
authors: Clarke
authors: Suzanne A
authors: SA
authors: Eccles
authors: Frank
authors: F
authors: Stieber
authors: Kai
authors: K
authors: Schiemann
authors: Julian
authors: J
authors: Blagg
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001681:Biological Assay / Q000379:methods; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008156:Luciferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000606523:CCT251545; D011725:Pyridines; D054852:Small Molecule Libraries; D013141:Spiro Compounds; D008156:Luciferases