Issa et al.. “Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study..” Lancet Oncology 16, no. 9 2015 Sep : 1099-110. DOI: 10.1016/S1470-2045(15)00038-8.

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Summary

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome.

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Issa et al.. “Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study..” Lancet Oncology 16, no. 9 2015 Sep : 1099-110. DOI: 10.1016/S1470-2045(15)00038-8.

Murray et al.. “Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.” ACS Med. Chem. Lett. 4 June 2015

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The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the “back-to-front” design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines.

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Murray et al.. “Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.” ACS Med. Chem. Lett. 4 June 2015

Erlanson et al.. “Twenty years on: the impact of fragments on drug discovery.” Nature Reviews Drug Discovery (2016)

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After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.

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Erlanson et al. “Twenty years on: the impact of fragments on drug discovery.” Nature Reviews Drug Discovery (2016) doi: 10.1038/nrd.2016.109

Ludlow et al.. “Detection of Secondary Binding sites in Proteins using Fragment Screening.” PNAS, 11 December 2015 (www.pnas.org/cgi/doi/10.1073/pnas.1518946112)

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Proteins need to be tightly regulated as they control biological processes in most normal cellular functions. The precise mechanisms of regulation are rarely completely understood but can involve binding of endogenous ligands and/or partner proteins at specific locations on a protein that can modulate function. Often, these additional secondary binding sites appear separate to the primary
binding site, which, for example for an enzyme, may bind a substrate.

In previous work, we have uncovered several examples in which secondary binding sites were discovered on proteins using fragment screening approaches. In each case, we were able to establish
that the newly identified secondary binding site was biologically relevant as it was able to modulate function by the binding of a small molecule. In this study, we investigate how often secondary
binding sites are located on proteins by analyzing 24 protein targets for which we have performed a fragment screen using X-ray crystallography.

Our analysis shows that, surprisingly, the majority of proteins contain secondary binding sites based on their ability to bind fragments. Furthermore, sequence analysis of these previously unknown
sites indicate high conservation, which suggests that they may have a biological function, perhaps via an allosteric mechanism.

Comparing the physicochemical properties of the secondary sites with known primary ligand binding sites also shows broad similarities indicating that many of the secondary sites may be druggable in nature with small molecules that could provide new opportunities to modulate potential therapeutic targets.

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Ludlow et al.. “Detection of Secondary Binding sites in Proteins using Fragment Screening.” PNAS, 11 December 2015 (www.pnas.org/cgi/doi/10.1073/pnas.1518946112)

Lebraud et al.. “In-gel activity-based protein profiling of a clickable covalent ERK1/2 inhibitor .” Mol. BioSyst., 2016,12, 2867-2874

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In-gel activity-based protein profiling (ABPP) offers rapid assessment of the proteome-wide selectivity and target engagement of a chemical tool. Here we demonstrate the use of the inverse electron demand Diels Alder (IEDDA) click reaction for in-gel ABPP by evaluating the selectivity profile and target engagement of a covalent ERK1/2 probe tagged with a trans-cyclooctene group. The chemical probe was shown to bind covalently to Cys166 of ERK2 using protein MS and X-ray crystallography, and displayed submicromolar GI50s in A375 and HCT116 cells. In both cell lines, the probe demonstrated target engagement and a good selectivity profile at low concentrations, which was lost at higher concentrations. The IEDDA cycloaddition enabled fast and quantitative fluorescent tagging for readout with a high background-to-noise ratio and thereby provides a promising alternative to the commonly used copper catalysed alkyne–azide cycloaddition.

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Lebraud et al.. “In-gel activity-based protein profiling of a clickable covalent ERK1/2 inhibitor.” Mol. BioSyst., 2016,12, 2867-2874 DOI: 10.1039/C6MB00367B

Day et al.. “The Synthesis of 3,3-Dimethyl Aza- and Diazaindolines Using a Palladium-Catalysed Intramolecular Reductive Cyclisation.” Thieme. 2015. DOI: 10.1055/s-0035-1560320

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A range of azaindolines was prepared in three steps from heterocyclic amines using halogenation, alkylation with 3-bromo-2-methylpropene, and a palladium-catalysed reductive cyclisation. The chemistry proved applicable to a multigram-scale operation.

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Day et al.. “The Synthesis of 3,3-Dimethyl Aza- and Diazaindolines Using a Palladium-Catalysed Intramolecular Reductive Cyclisation.” Thieme. 2015. DOI: 10.1055/s-0035-1560320

Verdonk et al. “Protein–Ligand Informatics Force Field (PLIff): Toward a Fully Knowledge Driven “Force Field” for Biomolecular Interactions.” J. Med. Chem., 2016, 59 (14), pp 6891–6902

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The Protein Data Bank (PDB) contains a wealth of data on nonbonded biomolecular interactions. If this information could be distilled down to nonbonded interaction potentials, these would have some key advantages over standard force fields. However, there are some important outstanding issues to address in order to do this successfully. This paper introduces the protein–ligand informatics “force field”, PLIff, which begins to address these key challenges (https://bitbucket.org/AstexUK/pli). As a result of their knowledge-based nature, the next-generation nonbonded potentials that make up PLIff automatically capture a wide range of interaction types, including special interactions that are often poorly described by standard force fields. We illustrate how PLIff may be used in structure-based design applications, including interaction fields, fragment mapping, and protein–ligand docking. PLIff performs at least as well as state-of-the art scoring functions in terms of pose predictions and ranking compounds in a virtual screening context.

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Verdonk et al. “Protein–Ligand Informatics Force Field (PLIff): Toward a Fully Knowledge Driven “Force Field” for Biomolecular Interactions.” J. Med. Chem., 2016, 59 (14), pp 6891–6902 DOI: 10.1021/acs.jmedchem.6b00716

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Chessari et al.. “Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP.” Journal of Medical Chemistry. 28 July 2015. DOI: 10.1021/acs.jmedchem.5b00706 .

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Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis and pro-survival signaling pathways whose deregulation is often associated with tumor genesis and tumor growth. IAPs have been proposed as targets for anticancer therapy, and a number of peptidomimetic IAP antagonists have entered clinical trials. Using our fragment-based screening approach, we identified nonpeptidic fragments binding with millimolar affinities to both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure-based hit optimization together with an analysis of protein–ligand electrostatic potential complementarity allowed us to significantly increase binding affinity of the starting hits. Subsequent optimization gave a potent nonalanine IAP antagonist structurally distinct from all IAP antagonists previously reported. The lead compound had activity in cell-based assays and in a mouse xenograft efficacy model and represents a highly promising start point for further optimization.

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Chessari et al.. “Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP.” Journal of Medical Chemistry. 28 July 2015. DOI: 10.1021/acs.jmedchem.5b00706 .

Amin et al. “NMR backbone resonance assignment and solution secondary structure determination of human NSD1 and NSD2.” Biomol NMR Assign, 29 June 2016

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Proteins of the NSD family are histone-methyl transferases with critical functions in the regulation of chromatin structure and function. NSD1 and NSD2 are homologous proteins that function as epigenetic regulators of transcription through their abilities to catalyse histone methylation. Misregulation of NSD1 and NSD2 expression or mutations in their genes are linked to a number of human diseases such as Sotos syndrome, and cancers including acute myeloid leukemia, multiple myeloma, and lung cancer. The catalytic domain of both proteins contains a conserved SET domain which is involved in histone methylation. Here we report the backbone resonance assignments and secondary structure information of the catalytic domains of human NSD1 and NSD2.

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Amin et al. “NMR backbone resonance assignment and solution secondary structure determination of human NSD1 and NSD2.” Biomol NMR Assign, 29 June 2016. doi: 10.1007/s12104-016-9691-x

Keserü et al. “Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia.” J. Med. Chem. April 2016

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Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function; it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry but is sometimes used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in academia. This Perspective explores many of the theoretical, practical, and strategic considerations that occur within FBDD programs, including the optimal size, complexity, physicochemical profile, and shape profile of fragments in FBDD libraries, as well as compound storage, evaluation, and screening technologies. This compilation of industry experience in FBDD will hopefully be useful for those pursuing FBDD in academia.

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Keserü et al. “Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia.” J. Med. Chem. April 2016, DOI: 10.1021/acs.jmedchem.6b00197