Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3

Böttcher, Jark; Dilworth, David; Reiser, Ulrich; Neumüller, Ralph A.; Schleicher, Michael; Petronczki, Mark; Zeeb, Markus; Mischerikow, Nikolai; Allali-Hassani, Abdellah; Szewczyk, Magdalena M.; Li, Fengling; Kennedy, Steven; Vedadi, Masoud; Baršytė-Lovejoy, Dalia; Brown, Peter J.; Huber, K.; Rogers, Catherine; Wells, Carrow; Fedorov, Oleg; Rumpel, Klaus; Zoephel, Andreas; Mayer, Moriz; Wunberg, Tobias; Böse, Dietrich; Zahn, Stephan K.; Arnhof, Heribert; Berger, Helmut; Reiser, Christoph; Hörmann, Alexandra; Krammer, Teresa; Corcokovic, Maja; Sharps, Bernadette; Winkler, Sandra; Häring, Daniela; Cockcroft, Xiaoling; Fuchs, Julian E.; Müllauer, Barbara; Weiss-Puxbaum, A.; Gerstberger, Thomas; Boehmelt, Guido; Vakoc, Christopher R.; Arrowsmith, C.H.; Pearson, Mark; McConnell, Darryl B.

doi:10.1038/s41589-019-0310-x

Cited by 70 publications

(83 citation statements)

References 43 publications

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“…3f did not bind to NSD2-PWWP1 mutants where aromatic cage residues Y233 or F266 were mutated to alanine, indicating binding at the methyl-lysine binding site (Figure S5). In agreement with a recent observation that high DMSO concentrations can limit the potency of PWWP ligands 20 , the K d value of 3f was measured as 3.4 ± 0.4 µM in an SPR experiment with 0.5% DMSO (Figure S6).…”

Section: Resultssupporting

confidence: 90%

Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2

Freitas

Szewczyk

et al. 2020

Preprint

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Increased activity of the lysine methyltrans-ferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a Kd of 3.4 μM and abrogates histone H3K36me2 binding in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.

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Section: Resultssupporting

confidence: 90%

Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2

Freitas

Szewczyk

et al. 2020

Preprint

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“…In this context, LBVS approaches have been combined under the framework of data fusion [ 104 , 105 ], targeting the search for new entities, drug repurposing, polypharmacology, and safety profile analysis [ 106 , 107 , 108 , 109 ]. With regard to SBVS, distinct methods have been examined to yield a “consensus scoring” [ 110 , 111 , 112 , 113 ], relying on three main strategies: (i) the same docked poses have been evaluated with different scoring functions to build the final ranking, (ii) the results obtained for an ensemble of different protein structures of the same target have been combined to obtain a final score, and (iii) multiple docking methods have been used against a single-protein structure [ 54 , 114 , 115 ].…”

Section: Parallel Lb and Sb Approachesmentioning

confidence: 99%

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Vázquez

Lopez

Gibert³

et al. 2020

Molecules

113

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Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of virtual libraries in the search of active compounds. Though LB and SB methods have found widespread application in the discovery of novel drug-like candidates, their complementary natures have stimulated continued efforts toward the development of hybrid strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery projects. In this review, we analyze the main strategies and concepts that have emerged in the last years for defining hybrid LB + SB computational schemes in VS studies. Particularly, attention is focused on the combination of molecular similarity and docking, illustrating them with selected applications taken from the literature.

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“…One of the most frequently discussed topics for its design is the size of the fragment library, which has a substantial impact on the early stages as it affects the time and monetary costs in addition to the outcome of FBDD projects. Interestingly, the majority of respondents in recent polls had up to 2,000 compounds in their fragment libraries [15,16], while recent successful FBDD campaigns had library sizes of between 1,000 and 2,000 compounds [17,18]. Besides an optimal library size, consideration is also given to the structural complexity, physicochemical profile, and shape profile of fragments [19].…”

Section: Introductionmentioning

confidence: 99%

How Size Matters: Diversity for Fragment Library Design

Shi

Itzstein

2019

Molecules

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Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for various therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW < 300) compounds. One of the first challenges in implementing a FBDD approach is the design of a fragment library, and more specifically, the choice of its size and individual members. A diverse set of fragments is required to maximize the chances of discovering novel hit compounds. However, the exact diversity of a certain collection of fragments remains underdefined, which hinders direct comparisons among different selections of fragments. Based on structural fingerprints, we herein introduced quantitative metrics for the structural diversity of fragment libraries. Structures of commercially available fragments were retrieved from the ZINC database, from which libraries with sizes ranging from 100 to 100,000 compounds were selected. The selected libraries were evaluated and compared quantitatively, resulting in interesting size-diversity relationships. Our results demonstrated that while library size does matter for its diversity, there exists an optimal size for structural diversity. It is also suggested that such quantitative measures can guide the design of diverse fragment libraries under different circumstances.

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Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3

Cited by 70 publications

References 43 publications

Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2

Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

How Size Matters: Diversity for Fragment Library Design

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