Biology subjects

Greger, L.

Publications and source records attributed to Greger, L..

5 recordsLinked to original sources

bioRxiv2026

Identification and SAR optimization of FBXO22-mediated TEAD Targeted Glue degraders

TEAD transcription factors are emerging oncology targets due to their function as key effectors of the Hippo signalling pathway, which is frequently dysregulated in cancer. Here, we report the discovery and development of potent, deep, and rapid-acting TEAD Targeted Glue degraders that leverage an aldehyde-mediated degron mechanism. Our compounds demonstrate exceptional on-pathway selectivity profiles and exhibit the expected Hippo signalling modulation. Mechanistically, we demonstrate that amine-based TEAD degrader scaffolds undergo extracellular conversion to the active aldehyde species, which mediate covalent engagement of FBXO22 C326, triggering TEAD proteasomal degradation. The degraders identified were able to be rationally and systematically optimised for both degradation potency and kinetics, achieving enhanced degradation profiles compared to previously reported FBXO22-targeting approaches, establishing design principles for this degrader class. Our findings highlight strategies for the structure activity relationship (SAR) and rational optimization of aldehyde-mediated degrons to generate novel precision molecular glue degraders against TEAD, a high value oncology target.

cancer biology↗

bioRxiv2025

Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept

Prospective discovery of molecular glues degraders for a specific therapeutic target protein of interest is an emerging strategy in drug discovery. Modification of pre-existing ligands with fragments that can alter the protein surface can lead to the creation of novel compounds ( targeted glues) able to induce neo-interactions between the target and an E3 ligase, resulting in targeted protein degradation. By screening a library of potential BRD9 targeted glue compounds, we have discovered a potent and selective, reversibly covalent BRD9 degrader, AMPTX-1. Co-immunoprecipitation-mass spectrometry experiments demonstrated that cell treatment with AMPTX-1 induces selective recruitment of BRD9 to the E3 ligase DCAF16. Degradation is dependent on the engagement of the surface Cys58 of DCAF16 and formation of a covalent adduct to DCAF16 is facilitated by the ternary complex formation with BRD9. BRD9 degradation is achieved in vivo after oral dosing, demonstrating that covalent recruitment of DCAF16 is a viable strategy for targeted protein degradation and can be achieved with drug-like, orally bioavailable compounds with promising in vivo activity.

biochemistry↗

bioRxiv2021

Transcriptomics data availability and reusability in the transition from microarray to next-generation sequencing

Over the last two decades, molecular biology has been changed by the introduction of high-throughput technologies. Data sharing requirements have prompted the establishment of persistent data archives. A standardized approach for recording and managing these data was first proposed in the Minimal Information About a Microarray Experiment (MIAME) guidelines. The Minimal Information about a high throughput nucleotide Sequencing Experiment (MINSEQE) proposal was introduced in 2008 as a logical extension of the guidelines to next-generation sequencing (NGS) technologies used for transcriptome analysis. We present a historical snapshot of the data-sharing situation focusing on transcriptomics data from both microarray and RNA-sequencing experiments published between 2009 and 2013, a period during which RNA-seq studies became increasingly popular for transcriptome analysis. We assess how much data from RNA-seq based experiments is actually available in persistent data archives, compared to data derived from microarray based experiments, and evaluate how these types of data differ. Based on this analysis, we provide recommendations to improve RNA-seq data availability, reusability, and reproducibility.

bioinformatics↗

bioRxiv2017

Pan-cancer study of heterogeneous RNA aberrations

We present the most comprehensive catalogue of cancer-associated gene alterations through characterization of tumor transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes project. Using matched whole-genome sequencing data, we attributed RNA alterations to germline and somatic DNA alterations, revealing likely genetic mechanisms. We identified 444 associations of gene expression with somatic non-coding single-nucleotide variants. We found 1,872 splicing alterations associated with somatic mutation in intronic regions, including novel exonization events associated with Alu elements. Somatic copy number alterations were the major driver of total gene and allele-specific expression (ASE) variation. Additionally, 82% of gene fusions had structural variant support, including 75 of a novel class called \"bridged\" fusions, in which a third genomic location bridged two different genes. Globally, we observe transcriptomic alteration signatures that differ between cancer types and have associations with DNA mutational signatures. Given this unique dataset of RNA alterations, we also identified 1,012 genes significantly altered through both DNA and RNA mechanisms. Our study represents an extensive catalog of RNA alterations and reveals new insights into the heterogeneous molecular mechanisms of cancer gene alterations.

genomics↗

bioRxiv2017

Comprehensive genome and transcriptome analysis reveals genetic basis for gene fusions in cancer

Gene fusions are an important class of cancer-driving events with therapeutic and diagnostic values, yet their underlying genetic mechanisms have not been systematically characterized. Here by combining RNA and whole genome DNA sequencing data from 1188 donors across 27 cancer types we obtained a list of 3297 high-confidence tumour-specific gene fusions, 82% of which had structural variant (SV) support and 2372 of which were novel. Such a large collection of RNA and DNA alterations provides the first opportunity to systematically classify the gene fusions at a mechanistic level. While many could be explained by single SVs, numerous fusions involved series of structural rearrangements and thus are composite fusions. We discovered 75 fusions of a novel class of inter-chromosomal composite fusions, termed bridged fusions, in which a third genomic location bridged two different genes. In addition, we identified 522 fusions involving non-coding genes and 157 ORF-retaining fusions, in which the complete open reading frame of one gene was fused to the UTR region of another. Although only a small proportion (5%) of the discovered fusions were recurrent, we found a set of highly recurrent fusion partner genes, which exhibited strong 5 or 3 bias and were significantly enriched for cancer genes. Our findings broaden the view of the gene fusion landscape and reveal the general properties of genetic alterations underlying gene fusions for the first time.

genetics↗