Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors

Varnes, Jeffrey; Geschwindner, Stefan; Holmquist, Christopher R.; Forst, Janet M.; Wang, Xia; Dekker, Niek; Scott, Clay W.; Tian, Gaochao; Wood, Michael W.; Albert, Jeffrey S.

doi:10.1016/j.bmcl.2015.10.100

Cited by 8 publications

(8 citation statements)

References 38 publications

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“…This process represents a highly successful fragment-assisted drug discovery approach (FADD). 30,31 ■ RESULTS AND DISCUSSION Protein Preparation. To identify BCL6 inhibitors that disrupt the interaction between BCL6 and cofactors, we attempted to prepare BCL6 BTB cofactors that bind to the lateral groove of the BCL6 BTB homodimer.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of a B-Cell Lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach

et al. 2017

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B-cell lymphoma 6 (BCL6) is a transcriptional factor that expresses in lymphocytes and regulates the differentiation and proliferation of lymphocytes. Therefore, BCL6 is a therapeutic target for autoimmune diseases and cancer treatment. This report presents the discovery of BCL6-corepressor interaction inhibitors by using a biophysics-driven fragment-based approach. Using the surface plasmon resonance (SPR)-based fragment screening, we successfully identified fragment 1 (SPR K = 1200 μM, ligand efficiency (LE) = 0.28), a competitive binder to the natural ligand BCoR peptide. Moreover, we elaborated 1 into the more potent compound 7 (SPR K = 0.078 μM, LE = 0.37, cell-free protein-protein interaction (PPI) IC = 0.48 μM (ELISA), cellular PPI IC = 8.6 μM (M2H)) by a structure-based design and structural integration with a second high-throughput screening hit.

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Section: ■ Introductionmentioning

confidence: 99%

Discovery of a B-Cell Lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach

et al. 2017

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“…Using fragment-based drug discovery (FBDD), − Kamada and coauthors conducted screens of 1494 fragment-sized molecules against four BCL6 BTB proteins: captured wt BCL6 BTB , captured mt BCL6 BTB , coupled wt BCL6 BTB and NeutrAvidin, using SPR. − From the identified hits, the authors chose 64 pan-active candidates and conducted full dose–responses. The binding of selected hits was confirmed by STD-NMR .…”

Section: Recent Development Of Bcl6btb Inhibitorsmentioning

confidence: 99%

Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond

Hwang

MacKerell

et al. 2021

J. Med. Chem.

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B-cell lymphoma 6 (BCL6) is a master regulator of germinal center formation that produce antibody-secreting plasma cells and memory B-cells for sustained immune responses. The BTB domain of BCL6 (BCL6BTB) forms a homodimer that mediates transcriptional repression by recruiting its corepressor proteins to form a biologically functional transcriptional complex. The protein–protein interaction (PPI) between the BCL6BTB and its corepressors has emerged as a therapeutic target for the treatment of DLBCL and a number of other human cancers. This Perspective provides an overview of recent advances in the development of BCL6BTB inhibitors from reversible inhibitors, irreversible inhibitors, to BCL6 degraders. Inhibitor design and medicinal chemistry strategies for the development of novel compounds will be provided. The binding mode of new inhibitors to BCL6BTB are highlighted. Also, the in vitro and in vivo assays used for the evaluation of new compounds will be discussed.

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“…AstraZeneca have also reported fragment-assisted hit identification for PDE10A inhibitors . In a somewhat different approach, hits identified in a fragment screen were used to guide compound selection from the hits generated in a parallel HTS.…”

Section: Fragments As a Basis For Pde Inhibitor Drug Discoverymentioning

confidence: 99%

“…38,39 AstraZeneca have also reported fragment-assisted hit identification for PDE10A inhibitors. 40 In a somewhat different approach, hits identified in a fragment screen were used to guide compound selection from the hits generated in a parallel HTS. This approach was chosen since fragment cocrystallization was not available for the project, making an entirely fragment based approach less attractive.…”

Section: ■ Fragments As a Basis For Pde Inhibitor Drug Discoverymentioning

confidence: 99%

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Fragment-Based Drug Discovery of Phosphodiesterase Inhibitors

Svensson

Bender

Bailey³

2017

J. Med. Chem.

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Phosphodiesterases are proving to be fruitful targets for drug discovery. At the same time fragment-based drug discovery has matured into a powerful and widely applied technique. In this communication we review the application of fragment-based drug discovery for the successful identification of novel 3',5'-cyclic nucleotide phosphodiesterase (PDE) inhibitors, concentrating on both experimental and computational strategies for fragment screening and hit-to-lead development. To this end, we also mine the open access databases ChEMBL and PDB for fragments showing PDE inhibitory activity, as well as SureChEMBL for recent PDE related patents, to provide a wider context for exploring fragment diversity. Together these approaches form an integrated experimental and computational platform to exploit fragment-based drug discovery for this important gene superfamily.

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Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors

Cited by 8 publications

References 38 publications

Discovery of a B-Cell Lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach

Discovery of a B-Cell Lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach

Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond

Fragment-Based Drug Discovery of Phosphodiesterase Inhibitors

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