title: Action at a distance: allostery and the development of drugs to target cancer cell metabolism.
abstract: Cancer cells must carefully regulate their metabolism to maintain growth and division under varying nutrient and oxygen levels. Compelling data support the investigation of numerous enzymes as therapeutic targets to exploit metabolic vulnerabilities common to several cancer types. We discuss the rationale for developing such drugs and review three targets with central roles in metabolic pathways crucial for cancer cell growth: pyruvate kinase muscle isozyme splice variant 2 (PKM2) in glycolysis, glutaminase in glutaminolysis, and mutations in isocitrate dehydrogenase 1 and 2 isozymes (IDH1/2) in the tricarboxylic acid cycle. These targets exemplify the drugging approach to cancer metabolism, with allosteric modulation being the common theme. The first glutaminase and mutant IDH1/2 inhibitors have entered clinical testing, and early data are promising. Cancer metabolism provides a wealth of novel targets, and targeting allosteric sites promises to yield selective drugs with the potential to transform clinical outcomes across many cancer types.
authors.affiliation: Agios Pharmaceuticals, Inc., 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: DeLaBarre
authors.affiliation: Agios Pharmaceuticals, Inc., 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hurov
authors.affiliation: Agios Pharmaceuticals, Inc., 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cianchetta
authors.affiliation: Agios Pharmaceuticals, Inc., 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Murray
authors.affiliation: Agios Pharmaceuticals, Inc., 38 Sidney Street, Cambridge, MA 02139, USA. Electronic address: lenny.dang@agios.com.
authors.forename: Lenny
authors.initials: L
authors.lastname: Dang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005972:Glutaminase; D007521:Isocitrate Dehydrogenase; D007527:Isoenzymes; D008565:Membrane Proteins; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins