title: Pharmacologic activation of PKM2 slows lung tumor xenograft growth.
abstract: Inactivation of the M2 form of pyruvate kinase (PKM2) in cancer cells is associated with increased tumorigenicity. To test the hypothesis that tumor growth may be inhibited through the PKM2 pathway, we generated a series of small-molecule PKM2 activators. The compounds exhibited low nanomolar activity in both biochemical and cell-based PKM2 activity assays. These compounds did not affect the growth of cancer cell lines under normal conditions in vitro, but strongly inhibited the proliferation of multiple lung cancer cell lines when serine was absent from the cell culture media. In addition, PKM2 activators inhibited the growth of an aggressive lung adenocarcinoma xenograft. These findings show that PKM2 activation by small molecules influences the growth of cancer cells in vitro and in vivo, and suggest that such compounds may augment cancer therapies.
authors.affiliation: Astex Pharmaceuticals, Inc., Salt Lake City, UT, USA.
authors.forename: K Mark
authors.initials: KM
authors.lastname: Parnell
authors.forename: Jason M
authors.initials: JM
authors.lastname: Foulks
authors.forename: Rebecca N
authors.initials: RN
authors.lastname: Nix
authors.forename: Adrianne
authors.initials: A
authors.lastname: Clifford
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bullough
authors.forename: Bai
authors.initials: B
authors.lastname: Luo
authors.forename: Anna
authors.initials: A
authors.lastname: Senina
authors.forename: David
authors.initials: D
authors.lastname: Vollmer
authors.forename: Jihua
authors.initials: J
authors.lastname: Liu
authors.forename: Virgil
authors.initials: V
authors.lastname: McCarthy
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Liu
authors.forename: Scott
authors.initials: S
authors.lastname: Pearce
authors.forename: Kevin
authors.initials: K
authors.lastname: Wright
authors.forename: Marc
authors.initials: M
authors.lastname: O'Reilly
authors.forename: Michael V
authors.initials: MV
authors.lastname: McCullar
authors.forename: Koc-Kan
authors.initials: KK
authors.lastname: Ho
authors.forename: Steven B
authors.initials: SB
authors.lastname: Kanner
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013963:Thyroid Hormones / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D001596:Benzylamines; D002352:Carrier Proteins; D008565:Membrane Proteins; D011720:Pyrazoles; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C587441:SGI-10067; C587442:SGI-9380