Djordje Müsil

Sequence Scanning Improves Accuracy for Antibody-Antigen and Molecular Glue Ternary Complex Co-Folding

Stephanie M. Linker, Tobias Ploetz, Andreas Evers, Djordje Müsil et autres

Accurately modeling biomolecular interactions is crucial for understanding biological function and can accelerate drug discovery efforts. Deep learning based co-folding methods such as AlphaFold3 and Boltz-2 can successfully predict many different biomolecular complexes. However, these models show lower success rates in predicting …

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Abstract 246: Discovery and mechanistic characterisation of the first oral bioavailable FEN1 inhibitor for treatment of HRD and EWS cancers and combination with various DDR inhibitors.

Lars T. Burgdorf, Julien Lefranc, Lucy V. Armstrong, Roch P. Boivin et autres

Abstract Flap endonuclease 1 (FEN1) has emerged as a critical target in the DNA damage response (DDR) landscape, particularly due to its synthetic lethal interactions with homologous recombination-deficient (HRD) cancers, such as those harboring BRCA mutations. Despite the therapeutic potential of FEN1 …

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Pushing the limits of hydrogen/deuterium exchange mass spectrometry to study protein:fragment low affinity interactions

Catarina Malta, Diana O. Silva, Ulrich Grädler, Pedro M. F. Sousa et autres

Characterization of protein-ligand interactions is essential for the pre-clinical development of drug candidates and Hydrogen/Deuterium Exchange Mass Spectrometry (HDX-MS) has emerged as a valuable tool in this process. HDX-MS has predominantly been employed with high affinity compounds with only a few examples …

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Discovery of ART5537: A Potent and Selective Small-Molecule Probe for EXO1

Sam E. Mann, Owen A. Davis, Jörg Bomke, Irina Cornaciu et autres

Abstract Exonuclease 1 (EXO1) is emerging as a target of interest in oncology due to its involvement in multifaceted DNA metabolic processes, particularly in homologous recombination (HR). Evidence is building that BRCA1-deficient cancers are sensitive to loss of EXO1, suggesting therapeutic potential …

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Phenotypic Hit Identification and Optimization of Novel Pan-TEAD and Subtype-Selective Inhibitors

Timo Heinrich, Alessia Gambardella, Daniel F. Schwarz, Jakub Gunera et autres

Abstract Aiming to identify novel inhibitors of YAP-TEAD-dependent transcription, we conducted a TEAD-reporter-based cellular screen, which yielded a 5-azaindole hit that significantly stabilized TEAD subtypes 2 and 4 in a thermal shift assay. During optimization, derivatives with diverse TEAD selectivity profiles were …

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MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686

Timo Heinrich, Daniel F. Schwarz, Carl Johan Petersson, Jakub Gunera et autres

Taking the structural information into account, we were able to tune the TEAD selectivity for a specific chemotype. However, different TEAD selectivity profiles did not affect the compound potency or efficacy in the NCI-H226 viability assay. Amides based on MSC-4106 or analogues …

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On the humanization of VHHs: Prospective case studies, experimental and computational characterization of structural determinants for functionality

Monica L. Fernández‐Quintero, Enrico Guarnera, Djordje Müsil, Lukas Pekar et autres

The humanization of camelid-derived variable domain heavy chain antibodies (VHHs) poses challenges including immunogenicity, stability, and potential reduction of affinity. Critical to this process are complementarity-determining regions (CDRs), Vernier and Hallmark residues, shaping the three-dimensional fold and influencing VHH structure and function. …

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Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold

Emma L. Carswell, Timo Heinrich, Carl Johan Petersson, Jakub Gunera et autres

The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are …

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Data from M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models

Michael P. Sanderson, Manja Friese‐Hamim, Gina Walter-Bausch, Michael Paul Busch et autres

Abstract Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the …

Supplementary Data from M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models

Michael P. Sanderson, Manja Friese‐Hamim, Gina Walter-Bausch, Michael Paul Busch et autres

Supplemental Data and Methods

Supplementary Data from M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models

Michael P. Sanderson, Manja Friese‐Hamim, Gina Walter-Bausch, Michael Paul Busch et autres

Supplemental Data and Methods

Data from M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models

Michael P. Sanderson, Manja Friese‐Hamim, Gina Walter-Bausch, Michael Busch et autres

Abstract Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the …