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A Data-Driven Perspective on Bioisostere Evaluation: Mapping the Benzene Bioisostere Landscape with BioSTAR.
The bioisostere landscape is continually expanding, with new scaffolds emerging as alternatives in drug design. Increasingly, medicinal chemists face the challenge of selecting and prioritising these bioisosteres, often relying on personal experience and anecdotal evidence. In this Perspective, we lay out a data-driven approach to analyze the bioisostere landscape, using benzene bioisosteres as a representative example, and quantitatively compare replacements based on their impact on bioactivity, solubility, and metabolic stability. To support the findings of the analysis, we highlight recent and particularly elegant examples of benzene bioisostere applications while identifying areas where further development could significantly benefit the community. By providing this Perspective and associated data-mining workflow (BioSTAR), we aim to support more informed decision-making in bioisosteric replacement selection in drug design and inspire future innovations in bioisostere design.
Steric control of signaling bias in the immunometabolic receptor GPR84.
Biased signaling in G protein-coupled receptors offers therapeutic promise, yet rational design of biased ligands remains challenging due to limited mechanistic understanding. Here, we report a molecular framework for controlling signaling bias at the immunometabolic receptor GPR84. We identified three structurally-matched ligands (OX04529, OX04954, and OX04539) with varying steric profiles that exhibit comparable Gi protein activation but dramatically different β-arrestin recruitment capacities. A high-resolution cryo-EM structure of GPR84-Gi in complex with OX04529, complemented by molecular dynamics simulations and targeted mutagenesis, revealed that steric interactions between ligand substituents and Leu3366.52 and Phe1875.47 indirectly disrupt a critical polar network involving Tyr3326.48, Asn1043.36 and Asn3627.45 essential for β-arrestin recruitment. Based on these insights, we developed a steric-dependent model that enabled rational design of G protein-biased agonists with predictable β-arrestin recruitment profiles. This mechanistic framework provides a blueprint for designing biased agonists with customized signaling profiles at GPR84 and potentially other class A GPCRs.
T cell engagers: expanding horizons in oncology and beyond.
BACKGROUND/INTRODUCTION: T cell engagers (TCEs) are engineered immunotherapeutic molecules designed to direct the body's immune system against tumour or infected cells by bridging T cells and their targets, triggering potent cytotoxic responses. Over the past decade, TCE-based therapies have gained momentum in oncology, resulting in several FDA approvals for haematologic malignancies and showing growing promise in solid tumours. OBJECTIVE: This review elaborates on TCE mechanisms of action, emphasising their ability to activate T cells, target tumour antigens, and modulate the tumour microenvironment. METHODS/RESULTS: We also delve into the clinical outcomes demonstrating TCE efficacy, alongside challenges such as cytokine release syndrome, antigen heterogeneity, and short half-lives. Recent advances in TCE design have incorporated multispecific constructs and conditional activation strategies and expansion in target molecules has enabled broadening applications to non-oncology indications like autoimmune and infectious diseases. Moreover, the use of artificial intelligence (AI) has also accelerated TCE discovery by identifying favourable epitope interactions, reducing immunogenicity risks, and enhancing overall design efficiency. CONCLUSIONS: Looking further, these advances open up a new era to redefine success for TCEs in both cancer and beyond, offering hope for more effective, safer immunotherapies.
Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer.
The CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), but its origins have been obscure. A few CRCs carry oncogenic (gain-of-function) mutations in isocitrate dehydrogenase IDH1. Whilst IDH1 is an established CRC driver gene, the low frequency of IDH1-mutant CRCs (about 0.5%) has meant that the effects and molecular covariates of those mutations have not been established. We first showed computationally that IDH2 is also a CRC driver. Using multiple public and in-house CRC datasets, we then identified IDH mutations at the hotspots (IDH1 codons 132 and IDH2 codons 140 and 172) frequently mutated in other tumour types. Somatic IDH mutations were associated with BRAF mutations and expression of mucinous/goblet cell markers, but not with KRAS mutations or MSI. All IDH-mutant CRCs were CIMP-positive, mostly at a high level. Cell and mouse models showed that IDH mutation was plausibly causal for DNA hypermethylation. Whilst the aetiology of hypermethylation generally remains unexplained, IDH-mutant tumours did not form a discrete methylation subcluster, suggesting that different underlying mechanisms can converge on similar final methylation phenotypes. Although further analysis is required, IDH mutations may be the first cause of hypermethylation to be identified in a common cancer type, providing evidence that CIMP and DNA methylation represent more than aging-related epiphenomena. Cautious exploration of mutant IDH inhibitors and DNA demethylating agents is suggested in managing IDH-mutant CRCs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Variation in phenotype, genotype, and somatic diversity among asexual Schmidtea mediterranea planarians
Most multicellular life reproduces sexually, utilizing a single-celled stage that acts as a genetic bottleneck. This bottleneck limits the evolution of selfish cell adaptations by ensuring all cells descend from a single progenitor. We investigated an obligately asexual strain of Schmidtea mediterranea planarians that reproduces by self-bisection and lacks a single-cell bottleneck. Using 2.5 yearlong data on planarian reproductive behavior combined with genotyping, we revealed two previously undescribed genetically distinct substrains within the CIW4 strain. One substrain showed reduced fitness, which correlated with substantial losses of heterozygosity and increased somatic diversity. By genotyping consecutive head offspring over multiple generations, we found that only ∼9% of potential de novo mutations were transmitted to the next generation via the tail, suggesting that fission acts as a genetic bottleneck. Our study uncovers significant diversity in a fissiparous animal and proposes how somatic diversity can be controlled in the absence of a single-cell bottleneck.
Supplementary Tables and Figures from A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in <i>IDH1</i>-Mutated Myeloid Malignancies
<p>Table S1: Pharmacokinetics of IVO+VEN and IVO+VEN+AZATable S2: Treatment characteristics across the four dose levels in the phase 1b study population.Table S3: Study medication adherence: (A), Adherence to protocol administered medications during DLT evaluation period (cycles 1 and 2) of protocol directed therapy. (B), Adherence to protocol administered medications during the first 12 months of protocol directed therapy.Table S4: Dose modifications in patients experiencing hematologic adverse events during the entire study period until data cut-off on March 15th, 2022.Table S5: Regions covered by institutional next-generation sequencing (NGS) interrogating the entire exonic or hotspot regions of 81-genes frequently mutated in myeloid malignancies.Table S6: Variants identified using targeted 81-gene myeloid NGS panelTable S7: CyTOF antibodies utilized.Figure S1: Molecular, cytogenetic, and IDH1 variants across the P1b study population. (A), Oncoprint of molecular mutations identified at diagnosis in 31 patients enrolled demonstrated a diverse molecular landscape. (B-C), Neither median mutation burden nor IDH1 VAF was significantly different between included disease types. (D), IDH1 variants differed across disease types, with R132C mutations most frequent at diagnosis in ND and R/R-AML. IDH1 R132L and R132S variants were not identified in patients with MDS or MPN. (E), Clonal hierarchy of baseline mutations assessed using bulk myeloid NGS panel on baseline samples.Figure S2: Pharmacokinetics of IVO+VEN or IVO+VEN+AZA (continued): (A), AUC 24 and (B), Cmax of IVO+VEN or IVO+VEN+AZA within each respective dose level demonstrated a decrease in the presence of IVO when assessed on C2D14 compared to sampling on C1D14 in the absence of co- occurring IVO administration.Figure S3: CONSORT diagram of study participantsFigure S4: Bone marrow response and recovery following IVO+VEN or IVO+VEN+AZA: (A), Bone marrow blast reduction following one cycle of therapy with IVO+AZA, or IVO+VEN+AZA among all patients with an adequate bone marrow samples (N=28). Three patients had inadequate/hypocellular EOC1 bone marrow aspirations and were excluded. One patient enrolled with MRD+ AML only. (B) Cycle lengths during the first four cycles of treatment. Patients treated with IVO+VEN had significantly shorter cycle lengths for cycle 1 compared to patients treated with IVO+VEN+AZA.Figure S5: Adverse events in patients treated with IVO+VEN or IVO+VEN+AZA: (A), Common adverse events occurring in four or more patients on study during the entire phase 1b study period demonstrated by grade, (B), by receipt of IVO+VEN vs. IVO+VEN+AZA, (C), and by dose level.Figure S6: Morphologic and MRD response to IVO+VEN in ND-AML. Morphologic response, MRD-MFC, and IDH1 ddPCR status by treatment cycle in patients with ND-AML treated with the doublet combination of IVO+VEN 400 or VEN 800Figure S7: Morphologic and MRD response to IVO+VEN+AZA in ND-AML. Morphologic response, MRD-MFC, and IDH1 ddPCR status by treatment cycle in patients with ND-AML treated with the triplet combination of IVO+VEN 400 or VEN 800 +AZAFigure S8: Morphologic and MRD response to IVO+VEN or IVO+VEN+AZA in R/R-AML. Morphologic response, MRD-MFC, and IDH1 ddPCR status by treatment cycle in patients with R/R-AML treated with IVO+VEN with or without AZAFigure S9: Response and outcome of patients treated with IVO+VEN or IVO+VEN+AZA. (A), Swimmer's plot of patients on study with IVO+VEN +/- AZA by dose level.Figure S10: Landmark overall survival analyses based on IDH1 mutation detection in CRc using ddPCR as though performed on patients at baseline. (A), Overall survival from treatment start. (B), Including patients surviving at least 3-months (correlating with end of cycle 3). (C), Including patients surviving at least 5- months (correlating with end of cycle 5). (D), Including patients surviving at least 7-months (correlating with end of cycle 7).Figure S11: Influence of biological pathways on survival following IVO+VEN or IVO+VEN+AZA treatment. (A), Overall survival by methylation mutations. (B), Overall survival by signaling mutations. (C), Overall survival in all patients with signaling mutations based upon receipt of IVO+VEN or IVO+VEN+AZA. (D), Overall survival in patients with AML and signaling mutations based upon receipt of IVO+VEN or IVO+VEN+AZA.Figure S12: Persistent mutations in a long-term responder with ND-AML identifies mutations within a CD16+ monocytic population. (A and B), DAb-seq analysis at diagnosis and in remission in a patient with ND-AML (accession #18) and co-occurring RUNX1 p. L204Q and IDH1 p.R132H mutations treated with IVO+VEN+AZA demonstrated treatment eliminated the majority of IDH1 and RUNX1 co-mutated cells. (C and D), The predominant population of CD34+ myeloblasts was eliminated with therapy, however residual cells containing IDH1 and RUNX1 in remission were clustered with a monocytic cell population with increased CD16 expression (C and D).Figure S13: Immunophenotypic shift occurring under treatment selection with targeted therapy. Multiparameter flow cytometry in a patient with ND-AML (accession #20) demonstrating an alternative CD34+ population expanding at relapse compared to baseline, consistent with a phenotypic shift at disease.Figure S14: Increased alternative antiapoptotic protein expression levels correlate with resistance to IVO+VEN+AZA. CyTOF analysis in a patient with ND-AML (accession #11) treated with IVO+VEN+AZA who initially attained CRc followed by disease progression. Increased alternative anti-apoptotic protein levels (BCL-xL and MCL1) were observed, in addition to increased CD44 levels.Figure S15: Increased BCL2 levels relative to alternative anti-apoptotic proteins is associated with ongoing response to IVO+VEN+AZA. CyTOF analysis in a patient with ND-AML (accession #26) treated with IVO+VEN+AZA with a durable response to treatment following 18 cycles of therapy. The patient had multiple CD34+ cell populations at diagnosis, with higher BCL2 levels relative to BCL-xL or MCL-1. Following 3 cycles of therapy, marked reduction in these blast populations were observed.Figure S16: Increased alternative anti-apoptotic protein expression is observed in maturing myeloid populations with monocytic differentiation. CyTOF analysis in a patient with R/R-AML (accession #10) treated with IVO+VEN with a durable response to treatment following 41 cycles of therapy. Following cycle 3 of treatment, an expanding CD34+ cell populations with increased BCL-xL and MCL-1 levels was observed with an associated maturing CD14+ monocytic immunophenotype.</p>
Supplementary Protocol from A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in <i>IDH1</i>-Mutated Myeloid Malignancies
<p>Supplementary protocol for "Phase Ib/II Investigator Initiated Study of the IDH1-mutant inhibitor ivosidenib (AG120) with the BCL2 inhibitor venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies"</p>
Neurodegenerative disease in C9orf72 repeat expansion carriers: population risk and effect of UNC13A.
The C9orf72 hexanucleotide repeat expansion (HRE) is the most common monogenetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurodegenerative disease incidence in C9orf72 HRE carriers has been studied using cohorts from disease-affected families or by extrapolating from population disease incidence, potentially introducing bias. Age-specific cumulative incidence of ALS and dementia was estimated using Kaplan-Meier and competing risk models in C9orf72 HRE carriers compared to matched controls in UK Biobank. Risk modification by UNC13A genotype was examined. Of 490,331 individuals with valid genetic data, 701 had >100 repeats in C9orf72 (median age 55 [IQR 48-62], follow-up 13.4 years [12.3-14.1]). The cumulative incidence of ALS or dementia was 66% [95% CI 57-73%] by age 80 in C9orf72 HRE carriers versus 5.8% [4.5-7.0%] in controls, or 58% [50-64%] versus 5.1% [4.1-6.4%] accounting for the competing risk of other-cause mortality. Forty-one percent of dementia incidence accrued between age 75-80. C-allele homozygosity at rs12608932 in UNC13A increased ALS or dementia risk in C9orf72 HRE carriers (hazard ratio 1.81 [1.18 - 2.78]). C9orf72 HRE disease was incompletely penetrant in this population-based cohort, with risk modified by UNC13A genotype. This has implications for counselling at-risk individuals and modelling expected phenoconversion for prevention trials.
Erythropoiesis in the human
Erythropoiesis is the production of haemoglobin-containing red blood cells for oxygen delivery to the tissues. Approximately 1-2 Ã- 1012red cells are produced each day, and this remarkable productivity under stable conditions is also complemented by the capacity for rapid and substantial expansion when required. This chapter describes the developmental origins of primitive and definitive erythropoiesis in the yolk sac, the fetal liver and the bone marrow. Our current understanding of the mechanisms of erythroid lineage specification from multipotent haemopoietic stem cells remains incomplete, but key erythroid-specific transcription factors are known to be critical in directing erythroid-specific transcription. Characteristic changes in morphology, gene expression and cell surface markers allow the identification of erythroid cells at different stages of their differentiation and maturation. At a system level, the hormone erythropoietin is the principal regulator of erythroid activity. Following upregulation of its transcription by Hypoxia-Inducible Factor, erythropoietin directs an expansion of the pool of erythroid precursors and accelerated red cell maturation. This, together with coordinated iron absorption and delivery, provides an appropriate response to hypoxia caused by reduced numbers of circulating red blood cells associated with a very wide spectrum of causes.
Widespread Changes in the Immunoreactivity of Bioactive Peptide T14 After Manipulating the Activity of Cortical Projection Neurons
Previous studies have suggested that T14, a 14-amino-acid peptide derived from acetylcholinesterase (AChE), functions as an activity-dependent signalling molecule with key roles in brain development, and its dysregulation has been linked to neurodegeneration in Alzheimer’s disease. In this study, we examined the distribution of T14 under normal developmental conditions in the mouse forebrain, motor cortex (M1), striatum (STR), and substantia nigra (SN). T14 immunoreactivity declined from E16 to E17 and further decreased by P0, then peaked at P7 during early postnatal development before declining again by adulthood at P70. Lower T14 immunoreactivity in samples processed without Triton indicated that T14 is primarily localised intracellularly. To explore the relationship between T14 expression and neuronal activity, we used mouse models with chronic silencing (Rbp4Cre-Snap25), acute silencing (Rbp4Cre-hM4Di), and acute activation (Rbp4Cre-hM3D1). Chronic silencing altered the location and size of intracellular T14-immunoreactive particles in adult brains, while acute silencing had no observable effect. In contrast, acute activation increased T14+ density in the STR, modified T14 puncta size near Rbp4Cre cell bodies in M1 layer 5 and their projections to the STR, and enhanced co-localisation of T14 with presynaptic terminals in the SN.
Ketosis regulates K+ ion channels, strengthening brain-wide signaling disrupted by age.
Aging is associated with impaired signaling between brain regions when measured using resting-state fMRI. This age-related destabilization and desynchronization of brain networks reverses itself when the brain switches from metabolizing glucose to ketones. Here, we probe the mechanistic basis for these effects. First, we confirmed their robustness across measurement modalities using two datasets acquired from resting-state EEG (Lifespan: standard diet, 20-80 years, N = 201; Metabolic: individually weight-dosed and calorically-matched glucose and ketone ester challenge, μ a g e = 26.9 ± 11.2 years , N = 36). Then, using a multiscale conductance-based neural mass model, we identified the unique set of mechanistic parameters consistent with our clinical data. Together, our results implicate potassium (K+) gradient dysregulation as a mechanism for age-related neural desynchronization and its reversal with ketosis, the latter finding of which is consistent with direct measurement of ion channels. As such, the approach facilitates the connection between macroscopic brain activity and cellular-level mechanisms.
Gamma activation spread reflects disease activity in amyotrophic lateral sclerosis.
OBJECTIVE: A non-invasive measure of cerebral motor system dysfunction would be valuable as a biomarker in amyotrophic lateral sclerosis (ALS). Task-based magnetoencephalography (tMEG) measures the magnetic fields generated by cortical neuronal oscillatory activity during task performance. Gamma activations are periods of high-power and high-frequency cortical oscillations integral to motor control. METHODS: tMEG was undertaken during 60 bilateral isometric hand grip exercises in ALS (n = 42) and compared with healthy controls (HC, n = 33). Gamma activation spread (GAS) was estimated by calculating the number of activated regions during each 100 ms time-bin and compared statistically between groups. Gamma activation patterns were visualised by plotting each participant's brain activity separately as a 2-dimensional video. RESULTS: There was no difference in grip strength between groups. GAS was greatly increased in the ALS group compared to HC (p