title: Identification of 3,6-disubstituted dihydropyrones as inhibitors of human lactate dehydrogenase.
abstract: A series of 3,6-disubstituted dihydropyrones were identified as inhibitors of human lactate dehydrogenase (LDH)-A. Structure activity relationships were explored and a series of 6,6-spiro analogs led to improvements in LDHA potency (IC50 <350 nM). An X-ray crystal structure of an improved compound bound to human LDHA was obtained and it illustrated additional opportunities to enhance the potency of these compounds, resulting in the identification of 51 (IC50=30 nM).
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Corson
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Charles Z
authors.initials: CZ
authors.lastname: Ding
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sharada
authors.initials: S
authors.lastname: Labadie
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Robarge
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: BinQing
authors.initials: B
authors.lastname: Wei
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Aihe
authors.initials: A
authors.lastname: Zhou
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011753:Pyrones; D007770:L-Lactate Dehydrogenase
keywords: LDHA; Tumor metabolism; X-ray crystal structure