Biology subjects

Bednarz, A.

Publications and source records attributed to Bednarz, A..

4 recordsLinked to original sources

bioRxiv2026

Discovery of CDK4-selective molecular glue degraders by high-throughput proteomics

Molecular glue degraders (MGDs) are proximity-inducing molecules that promote the destruction of disease-causing proteins by stabilizing novel interfaces between E3 ubiquitin ligases and target proteins. The rational design of MGDs remains exceptionally challenging, historically relying on serendipitous discoveries. Here, we deployed a high-throughput, mass spectrometry (MS)-based screen evaluating thousands of cereblon (CRBN)-directed compounds to expedite the identification of novel neosubstrates. This workflow led to the discovery of NE26394, a first-in-class MGD that selectively eliminates cyclin-dependent kinase 4 (CDK4), a critical oncogenic driver of cell cycle progression. Mechanistically, NE26394-induced CDK4 recognition by CRBN depends on the co-recruitment of endogenous INK4 family proteins. In CDK4-dependent cancer models, NE26394 effectively mimics the anti-proliferative RB-E2F pathway perturbations induced by clinical CDK4 inhibitors, rendering it an attractive candidate for further preclinical development.

biochemistry↗

bioRxiv2026

Integrated proteomic screening reveals design principles of CRBN molecular glue degraders

Cereblon (CRBN)-based molecular glue degraders (MGDs) induce the degradation of diverse disease-relevant proteins, underscoring their broad therapeutic potential. Here we systematically expand the CRBN neosubstrate landscape using a target-agnostic discovery approach. By integrating deep proteomic and ubiquitinomic profiling of a 960-compound library, we identify compound-induced ubiquitination and depletion of over 230 endogenous proteins. Among these, 124 represent previously unreported CRBN neosubstrates, with over half lacking a predicted G-loop degron. We provide this dataset via an interactive resource, NeosubstratesDB. Complementary cellular and biochemical assays mechanistically define the interaction domain of IRAK1 and establish G-loop-dependent degradation for BCL6. Interpretable machine learning (iML) integrating proteomic profiles with chemical structures highlights key molecular fingerprints driving neosubstrate selectivity for targets such as CSNK1A1, ZFP91 and WEE1. Together, these findings significantly expand the repertoire of CRBN neosubstrates and provide a framework for rational design of next-generation MGDs.

biochemistry↗

bioRxiv2024

Dose- and time-dependent effects of cobalt protoporphyrin IX on granulocyte mobilization and metabolic markers in mice

Recombinant granulocyte colony-stimulating factor (G-CSF) is the most commonly used agent for treating neutropenia and mobilizing hematopoietic stem cells (HSCs) for transplantation. However, some patients do not respond effectively to existing mobilization protocols. To address this, the development of new therapeutic approaches is necessary. One potential strategy is the pharmacological induction of endogenous mobilizing factors, which can be achieved through the administration of cobalt protoporphyrin IX (CoPP). CoPP induces mobilization of HSCs and granulocytes by increasing endogenous G-CSF production, though the optimal dosing and potential side effects remain unclear. The aim of our study was to optimize the dose and timing of CoPP administration and evaluate its safety in mobilizing cells from the bone marrow to the blood. Our results show that CoPP exerts a dose-dependent mobilizing effect, with the highest G-CSF levels and number of mobilized leukocytes observed in mice treated with 10 mg/kg of CoPP. While there were no severe adverse effects, there were mild fluctuations in markers of liver and kidney function, including a slight reduction in urea nitrogen (BUN) and glucose levels during the five days of administration. Additionally, although most parameters normalized within 30 days after treatment, the decrease in BUN persisted. Mice experienced short-term weight loss following CoPP administration, but they regained their initial weight within two weeks. By day 30, leukocyte counts, hematopoietic stem and progenitor cells (HSPCs) in bone marrow, and G-CSF concentration in the blood had returned to baseline. This study demonstrates that CoPP mobilizes cells from the bone marrow to the blood in a dose-dependent manner, with mild side effects, including temporary changes in biochemical markers and a sustained reduction in BUN levels.

pharmacology and toxicology↗

bioRxiv2023

Complex genomic landscape of inversion polymorphism in Europe's most destructive forest pest

In many species, polymorphic inversions underlie complex phenotypic polymorphisms and facilitate local adaptation in the face of gene flow. Multiple polymorphic inversions can co-occur in a genome, but the prevalence, evolutionary significance, and limits to complexity of genomic inversion landscapes remain poorly understood. Here, we examine genome-wide variation in one of Europes most destructive forest pests, the spruce bark beetle Ips typographus, scan for polymorphic inversions, and test whether inversions are involved in key adaptations in this species. We analyzed 240 individuals from 18 populations across the species European range and, using a whole-genome resequencing approach, identified 27 polymorphic inversions covering approximately 28% of the genome. The inversions vary in size and in levels of intra-inversion recombination, are highly polymorphic across the species range, and often overlap, forming a complex genomic architecture. We test several mechanisms, including directional selection, overdominance and associative overdominance that can contribute to the maintenance of inversion polymorphisms in the genome. We show that the heterogeneous inversion landscape is likely maintained by the combined action of several evolutionary forces and that inversions are enriched in odorant receptor genes encoding key elements of recognition pathways for host plants, mates, and symbiotic fungi. Our results indicate that the genome of this major forest pest of growing social, political, and economic importance harbors one of the most complex inversion landscapes described to date posing a question about limits of genomic architecture complexity.

evolutionary biology↗