title: Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors.
abstract: Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (K(d)) and enzyme inhibition (IC(50)) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139, USA. anna.kohlmann@ariad.com
authors.forename: Anna
authors.initials: A
authors.lastname: Kohlmann
authors.forename: Stephan G
authors.initials: SG
authors.lastname: Zech
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Tianjun
authors.initials: T
authors.lastname: Zhou
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Squillace
authors.forename: Lois
authors.initials: L
authors.lastname: Commodore
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Greenfield
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Lu
authors.forename: David P
authors.initials: DP
authors.lastname: Miller
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Huang
authors.forename: Jiwei
authors.initials: J
authors.lastname: Qi
authors.forename: R Mathew
authors.initials: RM
authors.lastname: Thomas
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wang
authors.forename: Sen
authors.initials: S
authors.lastname: Zhang
authors.forename: Rory
authors.initials: R
authors.lastname: Dodd
authors.forename: Shuangying
authors.initials: S
authors.lastname: Liu
authors.forename: Rongsong
authors.initials: R
authors.lastname: Xu
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Xu
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Miret
authors.forename: Victor
authors.initials: V
authors.lastname: Rivera
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhu
authors.forename: David C
authors.initials: DC
authors.lastname: Dalgarno
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006019:Glycolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D010085:Oxidative Phosphorylation; D011487:Protein Conformation; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004791:Enzyme Inhibitors; D007770:L-Lactate Dehydrogenase