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[Image: see text] In order to assess the potential of sPLA(2)-X as a therapeutic target for atherosclerosis, novel sPLA(2) 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.

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.

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.

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.

e13518 Background: By producing fructose-2,6-bisphosphate, PFKFB3 functions as an activator of anaerobic glycolysis. PFKFB3 is both over expressed and over activated in many of the types of human cancer. Specific inhibition of the PFKFB3 enzyme results in a reduction in metabolism and cell growth in oxygen-deficient cancer environments. Methods: High-throughput screening. Medicinal Chemistry. Structure-Based Drug Design, X-ray Crystallography. NMR. Isothermal Calorimetry. Dynamic Light Scatttering. ADME. Results: A high-throughput screening of 50.000 selected compounds, by means of a biochemical assay, generated 105 hits including both ATP-and non-ATP competitive hits as identified by NMR binding experiments. The latter type was prioritized and two hits with a similar “ring-linker-ring structure” were selected for further expansions. Interestingly, although structurally similar, the two hits were found by means of X-ray crystallography to exhibit different binding modes within the fructose pocket. Based on their respective binding mode, two chemical series were developed displaying different ADME properties and PFKFB isoenzyme selectivity. Calorimetry verified a reversible strong enthalpy driven, direct binding for both chemical series. A third chemical series was developed towards yet another unoccupied binding pocket within the fructose-site, yielding a 5-fold increase in potency. Strong interactions within the new pocket were confirmed using X-ray crystallography. Our PFKFB3 inhibitors were shown to reduce tumor cell growth in vitro and to exhibit combinatory effects with Cisplatin. Conclusions: We have targeted the fructose-binding pocket of PFKFB3, developed compounds with nM binding potency and have gained a detailed understanding of SAR via structural information. The structure-based analysis has provided a good understanding of the molecular interactions, which is important for further biological/clinical positioning: e.g., combination with chemotherapy, optimization of PK properties and proof of principle in vivo.