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

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

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.7b0015

Abstract

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

 

Lebraud et al., “Protein degradation: a validated therapeutic strategy with exciting prospects.” Essays in Biochemistry (2017) 61 517–527; DOI: 10.1042/EBC20170030

Abstract

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

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

Abstract

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

Hall et al., “The Fragment Network: A Chemistry Recommendation Engine Built Using a Graph Database.” J. Med. Chem., 2017, 60(14), pp 6440-6450, DOI: 10.1021/acs.jmedchem.7b00809

Abstract

The hit validation stage of a fragment-based drug discovery campaign involves probing the SAR around one or more fragment hits. This often requires a search for similar compounds in a corporate collection or from commercial suppliers. The Fragment Network is a graph database that allows a user to efficiently search chemical space around a compound of interest. The result set is chemically intuitive, naturally grouped by substitution pattern and meaningfully sorted according to the number of observations of each transformation in medicinal chemistry databases. This paper describes the algorithms used to construct and search the Fragment Network and provides examples of how it may be used in a drug discovery context.

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Hall et al., “The Fragment Network: A Chemistry Recommendation Engine Built Using a Graph Database.” J. Med. Chem., 2017, 60(14), pp 6440-6450, DOI: 10.1021/acs.jmedchem.7b00809

Tamanini et al., “Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP).” J. Med. Chem., 2017, 60(11), pp 4611-4625, DOI: 10.1021/acs.jmedchem.6b01877

 Abstract

XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies, and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology.

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Tamanini et al., “Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP).” J. Med. Chem., 2017, 60(11), pp 4611-4625, DOI: 10.1021/acs.jmedchem.6b01877

 

Rathi et al., “Predicting ‘Hot’ and ‘Warm’ Spots for Fragment Binding.” J. Med. Chem., 2017, 60 (9), pp 4036-4046, DOI: 10.1021/acs.jmedchem.7b00366

Abstract

Computational fragment mapping methods aim to predict hotspots on protein surfaces where small fragments will bind. Such methods are popular for druggability assessment as well as structure-based design. However, to date researchers developing or using such tools have had no clear way of assessing the performance of these methods. Here, we introduce the first diverse, high quality validation set for computational fragment mapping. The set contains 52 diverse examples of fragment binding “hot” and “warm” spots from the Protein Data Bank (PDB). Additionally, we describe PLImap, a novel protocol for fragment mapping based on the Protein–Ligand Informatics force field (PLIff). We evaluate PLImap against the new fragment mapping test set, and compare its performance to that of simple shape-based algorithms and fragment docking using GOLD. PLImap is made publicly available from https://bitbucket.org/AstexUK/pli.

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Rathi et al., “Predicting ‘Hot’ and ‘Warm’ Spots for Fragment Binding.” J. Med. Chem., 2017, 60 (9), pp 4036-4046, DOI: 10.1021/acs.jmedchem.7b00366

Johnson et al., “Fragment-to-Lead Medicinal Chemistry Publications in 2015.” J. Med. Chem., 2017, 60 (1), pp 89–99, DOI: 10.1021/acs.jmedchem.6b01123

Abstract

Fragment-based drug discovery (FBDD) is now well-established as a technology for generating new chemical leads and drugs. This Miniperspective provides a tabulated overview of the fragment-to-lead literature published in the year 2015, together with a commentary on trends observed across the FBDD field during this time. It is hoped that this tabulated summary will provide a useful point of reference for both FBDD practitioners and the wider medicinal chemistry community.

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Johnson et al. “Fragment-to-Lead Medicinal Chemistry Publications in 2015.” J. Med. Chem., 2017, 60 (1), pp 89–99, DOI: 10.1021/acs.jmedchem.6b01123