O’Reilly et al., “Crystallographic screening using ultra-low-molecular-weight ligands to guide drug design.” Drug Discovery Today, 2019; Doi.org/10.1016/j.drudis.2019.03.009
Ceska et al., “Cryo-EM in drug discovery” Biochemical Society Transactions (2019); 10.1042/BST20180267
Grainger et al., “Enabling Synthesis in Fragment-Based Drug Discovery by Reactivity Mapping: Photoredox-Mediated Cross-Dehydrogenative Heteroarylation of Cyclic Amines.” Chemical Science 2019; 10.1039/C8SC04789H
Lebraud., et al., “Quantitation of ERK1/2 inhibitor cellular target occupancies with a reversible slow off-rate probe.” Chem. Sci. October 2018, Issue 37; Doi.org/10.1039/c8sc02754d
Perera TPS, et al., “Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor.” Mol Cancer Ther, 2017, Vol 16, No. 6 pp. 1010– 1020. DOI: 10.1158/1535-7163.MCT-16-0589
Jubb, HC et al., “COSMIC-3D provides structural perspectives on cancer genetics for drug discovery.” Nature Genetics. 2018; DOI 10.1038/s41588-018-0214-9
Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP–XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate 27 (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423).
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Johnson et al., “A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-2-[(2R,5R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660).” J. Med. Chem., 2018, DOI: 10.1021/acs.jmedchem.8b00900
The RAS–RAF–MEK–ERK pathway has been intensively studied in oncology, with RAS known to be mutated in ∼30% of all human cancers. The recent emergence of ERK1/2 inhibitors and their ongoing clinical investigation demands a better understanding of ERK1/2 behavior following small-molecule inhibition. Although fluorescent fusion proteins and fluorescent antibodies are well-established methods of visualizing proteins, we show that ERK1/2 can be visualized via a less-invasive approach based on a two-step process using inverse electron demand Diels–Alder cycloaddition. Our previously reported trans-cyclooctene-tagged covalent ERK1/2 inhibitor was used in a series of imaging experiments following a click reaction with a tetrazine-tagged fluorescent dye. Although limitations were encountered with this approach, endogenous ERK1/2 was successfully imaged in cells, and “on-target” staining was confirmed by over-expressing DUSP5, a nuclear ERK1/2 phosphatase that anchors ERK1/2 in the nucleus.
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Sipthorp et al., ” Visualization of Endogenous ERK1/2 in Cells with a Bioorthogonal Covalent Probe.” Bioconjugate Chemistry, (JUN 2017) Vol. 28, No. 6, pp. 1677-1683; DOI: 10.1021/acs.bioconjchem.7b00152
In a time of unprecedented challenges in developing potent, selective and well-tolerated protein inhibitors as therapeutics, drug hunters are increasingly seeking alternative modalities to modulate pharmacological targets. Selective inhibitors are achievable for only a fraction of the proteome, and are not guaranteed to elicit the desired response in patients, especially when pursuing targets identified through genetic knockdown. Targeted protein degradation holds the potential to expand the range of proteins that can be effectively modulated. Drugs inducing protein degradation through misfolding or by modulating cereblon (CRBN) substrate recognition are already approved for treatment of cancer patients. The last decade has seen the development of proteolysis targeting chimeras (PROTACs), small molecules that elicit proteasomal degradation by causing protein polyubiquitination. These have been used to degrade a range of disease-relevant proteins in cells, and some show promising efficacy in preclinical animal models, although their clinical efficacy and tolerability is yet to be proven. This review introduces current strategies for protein degradation with an emphasis on PROTACs and the role of click chemistry in PROTAC research through the formation of libraries of preclicked PROTACs or in-cell click-formed PROTACs (CLIPTACs).
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Lebraud et al., “Protein degradation: a validated therapeutic strategy with exciting prospects.” Essays in Biochemistry (2017) 61 517–527; DOI: 10.1042/EBC20170030
Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind. Of the biophysical methods available for fragment screening, X-ray protein crystallography is one of the most sensitive and least prone to false positives. It also provides detailed structural information of the protein–fragment complex at the atomic level. Fragment-based screening using X-ray crystallography is therefore an efficient method for identifying binding hotspots on proteins, which can then be exploited by chemists and biologists for the discovery of new drugs. The use of FBDD is illustrated here with a recently published case study of a drug discovery programme targeting the challenging protein–protein interaction Kelch-like ECH-associated protein 1:nuclear factor erythroid 2-related factor 2.
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Price et al., “Fragment-based drug discovery and its application to challenging drug targets.” Essays in Biochemistry (2017) 61 475–484; DOI: 10.1042/EBC20170029