ABSTRACT
The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-γH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Biphenyl Compounds/pharmacology , Enzyme Inhibitors/pharmacology , Hydroxybenzoates/pharmacology , Neoplasms/therapy , Phosphofructokinase-2/antagonists & inhibitors , Sulfones/pharmacology , Antineoplastic Agents/therapeutic use , Biphenyl Compounds/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/radiation effects , Chemoradiotherapy/methods , DNA Breaks, Double-Stranded/radiation effects , Dideoxynucleotides/metabolism , Enzyme Inhibitors/therapeutic use , Humans , Hydroxybenzoates/therapeutic use , Phosphofructokinase-2/genetics , Phosphofructokinase-2/metabolism , RNA, Small Interfering/metabolism , Radiation Tolerance/drug effects , Radiation Tolerance/genetics , Radiation, Ionizing , Recombinational DNA Repair/drug effects , Recombinational DNA Repair/radiation effects , Sulfones/therapeutic useABSTRACT
In order to assess the potential of sPLA2-X as a therapeutic target for atherosclerosis, novel sPLA2 inhibitors with improved type X selectivity are required. To achieve the objective of identifying such compounds, we embarked on a lead generation effort that resulted in the identification of a novel series of indole-2-carboxamides as selective sPLA2-X inhibitors with excellent potential for further optimization.
ABSTRACT
Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties.
Subject(s)
Antineoplastic Agents/pharmacology , DNA Repair Enzymes/antagonists & inhibitors , Morpholines/pharmacology , Phosphoric Monoester Hydrolases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Caco-2 Cells , Cell Membrane Permeability , Drug Design , Drug Discovery , Drug Evaluation, Preclinical , Hepatocytes/metabolism , Humans , Mice , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Morpholines/chemistry , Morpholines/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
The discovery of potent novel pyrazole containing group X secreted phospholipase A2 inhibitors via structure based virtual screening is reported. Docking was applied on a large set of in-house fragment collection and pharmacophore feature matching was used to filter docking poses. The selected virtual screening hits was run in NMR screening, a potent pyrazole containing fragment hit was identified and confirmed by its complex X-ray structure and the following biochemical assay result. Expansion on the fragment hit has led to further improvement of potency while maintaining high ligand efficiency, thus supporting the further development of this chemical series.
Subject(s)
Group X Phospholipases A2/chemistry , Phospholipase A2 Inhibitors/chemistry , Pyrazoles/chemistry , Binding Sites , Databases, Protein , Drug Evaluation, Preclinical , Group X Phospholipases A2/metabolism , Humans , Molecular Docking Simulation , Phospholipase A2 Inhibitors/metabolism , Protein Structure, Tertiary , Pyrazoles/metabolismABSTRACT
Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.
