title: Discovery of 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide activators of the M2 isoform of pyruvate kinase (PKM2).
abstract: Activators of the pyruvate kinase M2 (PKM2) are currently attracting significant interest as potential anticancer therapies. They may achieve a novel antiproliferation response in cancer cells through modulation of the classic 'Warburg effect' characteristic of aberrant metabolism. In this Letter, we describe the optimization of a weakly active screening hit to a structurally novel series of small molecule 3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as potent PKM2 activators.
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA. Electronic address: yxu22@hotmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Liu
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Pearce
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Foulks
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: K Mark
authors.initials: KM
authors.lastname: Parnell
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Adrianne
authors.initials: A
authors.lastname: Clifford
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Rebecca N
authors.initials: RN
authors.lastname: Nix
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bullough
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Hendrickson
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wright
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: McCullar
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Kanner
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, USA.
authors.forename: Koc-Kan
authors.initials: KK
authors.lastname: Ho
mesh_terms: D002352:Carrier Proteins / Q000819:agonists / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins / Q000819:agonists / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000819:agonists / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins
keywords: 3-(Trifluoromethyl)-1H-pyrazole-5-carboxamides; Bioisostere; Cancer metabolism; PKM2 activator; Pyruvate kinase M2