Summary

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

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Woolford et al. “Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.” J Med Chem, 27 May 2016. DOI: 10.1021/acs.jmedchem.6b00212

Summary

KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch–NRF2 interaction. X-ray crystallographic screening identified three distinct “hot-spots” for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1–NRF2 interaction.

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Davies et al. “Mono-acidic inhibitors of the KEAP1 Kelch-NRF2 protein-protein interaction with high cell potency identified by Fragment-based Discovery.” J Med Chem, 31 March 2016. DOI: 10.1021/acs.jmedchem.6b00228

Summary

What’s a good fragment? Fragment-based drug discovery is well-established within many pharmaceutical, biotech, and academic institutions for generating new drugs. In this Essay, the opportunities and challenges for organic chemists to design and synthesize new fragments are described.

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Murray et al.. “Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD).” Angewandte Chemie. 3 November 2015. DOI: 10.1002/anie.201506783 .

Howard et al. “Fragment-Based Discovery of 6-Azaindazoles As Inhibitors of Bacterial DNA Ligase.” ACS Medicinal Chemistry Letters (2013). DOI: 10.1021/ml4003277 .

Crawford et al.. “SAHA abrogates FLIP-mediated inhibition of SMAC mimetic-induced apoptosis in mesothelioma.” Cell Death Dis. 2013 Jul; 4(7): e733 .