Biology subjects

Malik, B.

Publications and source records attributed to Malik, B..

6 recordsLinked to original sources

bioRxiv2026

Stereoselective Covalent Inhibitor of the Ovarian Cancer-Driving Transcription Factor PAX8

Transcription factors remain among the most challenging therapeutic targets in part because they lack well-defined ligandable binding pockets. We recently showed that aberrantly reactive cysteines in transcription factors can be directly targeted with electrophilic small molecules to induce selective transcription factor destabilization and degradation. Here, we extend this strategy to the lineage-defining oncogenic transcription factor PAX8, a critical driver of ovarian cancer. Screening of a chemically diverse library of more than 3,000 cysteine-reactive compounds against an endogenously HiBiT-tagged PAX8 reporter identified a sulfinyl aziridine chemotype that selectively reduced PAX8 abundance. Structure-activity and stereochemical analyses revealed highly enantio- and diastereoselective activity, identifying KL6-159A as the lead compound. Quantitative proteomics demonstrated selective loss of PAX8, while cellular thermal shift analysis and chemoproteomic profiling established direct covalent engagement of PAX8 at cysteine C57. Mutation of C57 completely abolished KL6-159A-induced PAX8 depletion, demonstrating that this residue is essential for compound activity. Transcriptomic profiling revealed broad suppression of the PAX8 transcriptional program, with FOXM1 emerging as the most significantly downregulated regulatory network together with numerous established PAX8 target genes. Collectively, these studies establish direct covalent engagement, transcriptional inhibition, and destabilization of PAX8 and further demonstrate the generality of covalent chemoproteomic approaches for drugging previously intractable transcription factors.

biochemistry↗

bioRxiv2025

Conserved Aberrant Developmental Trajectories of Human and Mouse SBMA Motor Neurons

Spinal bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine repeat expansion in the androgen receptor gene (AR). Lower motor neuron loss is a key feature of the disease, yet it remains poorly understood why these cells are affected. The transcriptional mechanisms underlying SBMA pathogenesis and how these evolve across developmental and disease stages remains incompletely defined. To elucidate the molecular mechanisms underlying motor neuron loss in SBMA, we first performed transcriptomic profiling of both induced pluripotent stem cell derived motor neurons (iPSC-MNs) generated from SBMA patients and laser-captured micro dissected motor neurons (LCM-MNs) from symptomatic AR100 SBMA mice. We compared differential gene expression between the two models to identify shared transcriptional programs. To address the temporal progression of molecular changes we conducted profiling at key stages of motor neurogenesis in the developing iPSC-MNs and at pre-symptomatic and end-stage disease in AR100 SBMA mice to elucidate the emergence of the transcriptional phenotype and the trajectory of the gene expression changes. We found significant transcriptional convergence between these two species. Notably, shared dysregulation was observed in pathways related to the spliceosome, the cell cycle and mitochondrial function. These transcriptional alterations emerged early in motor neurogenesis suggesting a developmental component to SBMA. Further in AR100 LCM-MNs we also observed disruption of mitochondrial and DNA damage repair pathways from pre-symptomatic to end stage disease. This study identifies conserved pathogenic mechanisms across two SBMA model systems and provides crucial insights into the molecular basis and temporal dynamics of SBMA progression which may help identify potential therapeutic targets for SBMA. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/674754v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1577034org.highwire.dtl.DTLVardef@187824eorg.highwire.dtl.DTLVardef@17bf6a5org.highwire.dtl.DTLVardef@17e09f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Identification and Characterization of PLUTO-201, a Novel Long Non-Coding RNA Associated with Poor Outcomes in Prostate Cancer

Background: Despite extensive investigation, the factors promoting aggressive prostate cancer are poorly understood. In particular, despite a few prominent examples, the role of long non-coding RNAs (lncRNAs) is largely unknown. Methods: We performed a comprehensive analysis of whole-genome transcriptome data to identify differential expression across 1,567 patients with prostate cancer, then correlated differential expression with risk of metastatic recurrence. We characterized the lncRNA most associated with metastasis in vitro and in vivo to investigate the mechanism by which it promotes aggressive prostate cancer. Results: We have identified a novel lncRNA, Prostate Cancer Associated hnRNPK Interacting Transcript (PCAHIT), which is strongly associated with metastasis and poor overall survival in men with prostate cancer. We find that overexpression/knockdown of PCAHIT in pre-clinical models of prostate cancer modulates proliferation rates and markers of an aggressive phenotype through regulation of steroid biosynthesis and expression of the MHC class I complex, driving increased growth in androgen-depleted conditions and decreased susceptibility to T cell-mediated cytotoxicity. We further find that the heterogeneous nuclear ribonucleoprotein hnRNPK directly binds PCAHIT and is indispensable for its activity. Conclusions: Overall, our findings indicate that PCAHIT is a driver of aggressive prostate cancer phenotypes and poor clinical outcomes through suppression of the immune response and increased androgen-independent cancer growth. PCAHIT is a potential biomarker of aggressive disease.

cancer biology↗

bioRxiv2025

Processivity and BDNF-dependent modulation of signalling endosome axonal transport are impaired in aged mice

A healthy nervous system is reliant upon an efficient transport network to deliver essential cargoes throughout the extensive and polarised architecture of neurons. The trafficking of cargoes, such as organelles and proteins, is particularly challenging within the long projections of neurons, which, in the case of axons, can be more than four orders of magnitude longer than cell bodies. It is therefore unsurprising that disruptions in axonal transport have been reported across neurological diseases. A decline in this essential process has also been identified in many aging models, perhaps compounding age-related neurodegeneration. Via intravital imaging, we recently determined that, despite a reduction in overall motility, the run speed and displacement of anterograde mitochondrial transport were unexpectedly enhanced in aged mouse peripheral nerves. Here, to determine how aging impacts a different axonal cargo, we evaluated in vivo trafficking of signalling endosomes in motor axons of mouse sciatic nerves from 3 to 22 months. Contrasting with mitochondria, we did not detect alterations in signalling endosome speed, but found a consistent rise in pausing that manifested after 18 months. We then treated muscles with brain-derived neurotrophic factor (BDNF), which regulates axonal transport of signalling endosomes in motor neurons; however, we observed no change in the processivity defect at 22 months, consistent with downregulation of the BDNF receptor TrkB at the neuromuscular junction. Together, these findings indicate that aging negatively impacts signalling endosome trafficking in motor axons likely through dampened BDNF signalling at the motor neuron-muscle interface. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/635507v1_ufig1.gif" ALT="Figure 1"> View larger version (84K): org.highwire.dtl.DTLVardef@d5fe63org.highwire.dtl.DTLVardef@13033c2org.highwire.dtl.DTLVardef@19621dcorg.highwire.dtl.DTLVardef@189121a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Consumption of human-relevant levels of sucrose-water rewires macronutrient uptake and utilization mechanisms in a tissue specific manner

Consumption of sugar-sweetened beverages (SSBs) have been linked to metabolic dysfunction, obesity, diabetes and enhanced risk of cardiovascular diseases across all age-groups globally. Decades of work that have provided insights into pathophysiological manifestations of sucrose overfeeding have employed paradigms that rarely mimic human consumption of SSBs. Thus, our understanding of multi-organ cross-talk and molecular and/or cellular mechanisms, which operate across scales and drive physiological derangement is still poor. By employing a paradigm of sucrose water feeding in mice that closely resembles chronic SSB consumption in humans (10% sucrose in water), we have unraveled hitherto unknown tissue-specific mechanistic underpinnings, which contribute towards perturbed physiology. Our findings illustrate that systemic impaired glucose homeostasis, mediated by hepatic gluconeogenesis and insulin resistance, does not involve altered gene expression programs in the liver. We have discovered the pivotal role of the small intestine, which in conjunction with liver and muscles, drives dyshomeostasis. Importantly, we have uncovered rewiring of molecular mechanisms in the proximal intestine that is either causal or consequential to systemic ill-effects of chronic sucrose water consumption including dysfunction of liver and muscle mitochondria. Tissue-specific molecular signatures, which we have unveiled, clearly indicate that inefficient utilization of glucose is exacerbated by enhanced uptake by the gut. Besides providing systems-wide mechanistic insights, we propose that consumption of SSBs causes intestinal molecular addiction for deregulated absorption of hexose-sugars, and drives diseases such as diabetes and obesity.

physiology↗

bioRxiv2019

Plasma pNfH differentiate SBMA from ALS

Background and aimSpinal bulbar muscular atrophy (SBMA) is a progressive adult-onset X-linked neuromuscular disease. Although traditionally considered a motor neuron disorder, recent advances have highlighted a primary myopathic component. We evaluated levels of phosphorylated neurofilament heavy chain (pNfH), a known biomarker for neurodegeneration, in SBMA. Materials and methodsWe collected plasma and serum from 46 SBMA, 50 ALS and 50 healthy control cases, alongside with plasma from a mouse model of SBMA (AR100) and littermate controls. We measured pNfH plasma levels using Single molecule array (Simoa), we assessed functional scales and we gathered demographic data. We analysed data using Mann-Whitney U test, Kruskal-Wallis test and Cox regression analysis. ResultsPlasma pNfH levels were significantly increased in ALS, but, intriguingly, there was no change in SBMA. These results were also confirmed in SBMA mice. The ROC curve highlighted that pNfH levels can effectively distinguish between ALS and SBMA (AUC 0.95). ConclusionsUnexpectedly, levels of pNfH are normal in SBMA, whilst they are increased in ALS, and suggest pNfH could serve as a biomarker to differentiate the two diseases. Further, this finding is in agreement with recent evidence showing that primary muscle damage is a crucial feature in SBMA.

neuroscience↗