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The t(8;21) chromosomal translocation activates aberrant expression of the AML1‐ETO (AE) fusion protein and is commonly associated with core binding factor acute myeloid leukaemia (CBF AML). Combining a conditional mouse model that closely resembles the slow evolution and the mosaic AE expression pattern of human t(8;21) CBF AML with global transcriptome sequencing, we find that disease progression was characterized by two principal pathogenic mechanisms. Initially, AE expression modified the lineage potential of haematopoietic stem cells (HSCs), resulting in the selective expansion of the myeloid compartment at the expense of normal erythro‐ and lymphopoiesis. This lineage skewing was followed by a second substantial rewiring of transcriptional networks occurring in the trajectory to manifest leukaemia. We also find that both HSC and lineage‐restricted granulocyte macrophage progenitors (GMPs) acquired leukaemic stem cell (LSC) potential being capable of initiating and maintaining the disease. Finally, our data demonstrate that long‐term expression of AE induces an indolent myeloproliferative disease (MPD)‐like myeloid leukaemia phenotype with complete penetrance and that acute inactivation of AE function is a potential novel therapeutic option. Graphical Abstract This novel model system of AML1‐ETO driven acute myeloid leukaemia addresses the concept of ‘oncogene addiction’. Better understanding of AML1‐ETO need to maintain leukemia and rewire the transcriptome may help to design future therapies.

Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q myelodysplastic syndromes (5q MDS), and it functions as a molecular glue for the protein degradation of neosubstrates by CRL4 CRBN . Proteolysis-targeting chimeras (PROTACs) using IMiDs with a target protein binder also induce the degradation of target proteins. The targeted protein degradation (TPD) of neosubstrates is crucial for IMiD therapy. However, current IMiDs and IMiD-based PROTACs also break down neosubstrates involved in embryonic development and disease progression. Here, we show that 6-position modifications of lenalidomide are essential for controlling neosubstrate selectivity; 6-fluoro lenalidomide induced the selective degradation of IKZF1, IKZF3, and CK1α, which are involved in anti-haematological cancer activity, and showed stronger anti-proliferative effects on MM and 5q MDS cell lines than lenalidomide. PROTACs using these lenalidomide derivatives for BET proteins induce the selective degradation of BET proteins with the same neosubstrate selectivity. PROTACs also exert anti-proliferative effects in all examined cell lines. Thus, 6-position-modified lenalidomide is a key molecule for selective TPD using thalidomide derivatives and PROTACs. Lenalidomide is effective for treating several hematological cancers but has teratogenic effect on the fetus. Here, the authors identify modifications that make lenalidomide more selective and effective when used as a stand-alone molecular glue or integrated in PROTACs.

The discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic chemotherapy to a personalised medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biology and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small molecule cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chemical hit and lead generation; lead optimization to identify a clinical drug candidate; and finally hypothesis-driven, biomarker-led clinical trials. Although all of these steps are critical, we view target validation and selection and the conduct of biology-directed clinical trials as especially important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clinical development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and technical challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solutions to overcome the ‘Valley of Death’ between basic research and approved medicines. We envisage a future in which addressing these challenges will enhance our rapid progress towards truly personalised medicine for cancer patients. ► Here we review small molecule cancer drug discovery and development. ► We focus on Target selection, hit identification, lead optimization and clinical trials. ► A particular emphasis of this article is personalized medicine.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.

In order to identify new treatment modalities and targets for the treatment of bladder cancer (BLC), we have searched the literature (PubMed) for circular RNAs (circRNAs) that mediate efficacy in preclinical BLC-related in vivo systems. Pathogenesis-affecting circRNAs can be up-regulated or down-regulated depending on their function as oncogenes or tumor suppressors. We have grouped the identified circRNAs according to functional aspects or protein categories, such as involvement in drug resistance, transmembrane proteins, secreted proteins, mediators of signaling, enzymes with pathogenic potential, transcription factors, as well as circRNAs involved in microRNA (miR) processing and epigenetic modifications. The identified up-regulated targets can be modulated with small molecules or antibody-based drugs depending on their druggability. Down-regulated circRNAs can potentially be reconstituted by replacement therapy, whereas up-regulated circRNAs can be inhibited by nucleic acid (NA)-based inhibitors. The validity of the approach of exploring circRNAs and their corresponding targets for therapeutic intervention was underlined by the identification of circRNAs that up-regulate fibroblast growth factor receptors, which can be inhibited by erdafitinib, an approved agent for the treatment of bladder cancer.

Background Radiotherapy resistance limits colorectal cancer (CRC) treatment efficacy, with only 15%–20% of patients achieving a complete response. Validated biomarkers predicting treatment response and serving as therapeutic targets are critically needed. Methods We performed integrative multiomics analysis of 200 CRC patients (GSE87211) with independent validation in 58 patients (GSE46862). Single‐cell RNA sequencing of 63,689 cells (GSE132465) determined cell‐type‐specific expression. Functional validation was conducted in radiotherapy‐resistant CRC cell lines through loss‐of‐function experiments including proliferation, migration/invasion, and radiosensitivity assays. Results FKBP10 emerged as the only gene achieving statistical significance in both discovery (log2FC = 0.74, p = 0.0007) and validation (log2FC = 0.52, p = 0.032) cohorts among 48 radioresistance‐associated genes. Single‐cell profiling revealed that FKBP10 was predominantly expressed in cancer‐associated fibroblasts (CAFs, 51.5% of stromal cells), implicating CAF‐mediated stromal remodeling in resistance. FKBP10 knockdown significantly inhibited proliferation, colony formation (35%–40% reduction), migration (30%), and invasion (50%), while markedly enhancing radiosensitivity through increased DNA damage (γH2AX foci increased twofold, p < 0.01) and strand breaks (comet tail DNA: 22% → 43%, p < 0.01). Conclusions This multiomics study establishes FKBP10 as a robust CAF‐derived biomarker and functional therapeutic target for radiotherapy resistance in CRC, providing a foundation for developing FKBP10‐targeted combination strategies for precision cancer treatment.

Acute myeloid leukemia (AML) is a genetically extremely heterogeneous disease. Drug resistance after induction therapy is a very frequent event resulting in poor medium survival times. Therefore, the identification of new targets and treatment modalities is a medical high priority issue. We addressed our attention to circular RNAs (circRNAs), which can act as oncogenes or tumor suppressors in AML. We searched the literature (PubMed) and identified eight up-regulated and two down-regulated circ-RNAs with activity in preclinical in vivo models. In addition, we identified twenty-two up-regulated and four down-regulated circRNAs with activity in preclinical in vitro systems, but pending in vivo activity. Up-regulated RNAs are potential targets for si- or shRNA-based approaches, and down-regulated circRNAs can be reconstituted by replacement therapy to achieve a therapeutic benefit in preclinical systems. The up-regulated targets can be tackled with small molecules, antibody-based entities, or other modes of intervention. For down-regulated targets, up-regulators must be identified. The ranking of the identified circRNAs with respect to therapy of AML will depend on further target validation experiments.

Celastrol (CEL) is a natural pentacyclic triterpenoid demonstrating significant therapeutic properties against various diseases. However, the ambiguity of target information poses a significant challenge in transitioning CEL from a traditional remedy to a modern pharmaceutical agent. Recently, the emerging target discovery approaches of natural products have broadened extensive avenues for uncovering comprehensive target information of CEL and promoting its drug development. Herein, diverse target discovery strategies are overviewed for the pharmacological and toxicological studies of CEL, including chemical proteomics, protein microarray, degradation‐based protein profiling, proteome‐wide label‐free approaches, network pharmacology, target‐based drug screening, multi‐omics analysis, and hypothesis‐driven target confirmation. Dozens of CEL targets have been identified, which significantly suggests that CEL functions as a multi‐target therapeutic agent. Further network interaction analysis and frequency analysis of collected targets reveal that PRDXs, HMGB1, HSP90, STAT3, and PKM2 may serve as key targets for CEL. Additionally, this review highlights the positive role of target discovery in facilitating CEL‐based combination therapy and drug delivery, which is essential for further advancing the clinical applications of CEL. Efforts in CEL target identification not only aid in unraveling the scientific underpinnings of its multiple pharmacological effects but also offer crucial insights for further drug development of CEL‐based drugs. Using celastrol as a case study, this review summarizes various target discovery strategies for natural products, including chemical proteomics, protein microarray, degradation‐based protein profiling, proteome‐wide label‐free approaches, network pharmacology, target‐based drug screening, and indirect strategies. It emphasizes the critical importance of the target discovery platforms and identified target information in bioactivity discovery, mechanism of action clarification, toxicity assessment, combination therapy, drug delivery, and clinical application of celastrol.

OBJECTIVE:--We examined the association between depression, measured as either a continuous symptom severity score or a clinical disorder variable, with self-care behaviors in type 2 diabetes. RESEARCH DESIGN AND METHODS--We surveyed 879 type 2 diabetic patients from two primary care clinics using the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), the Summary of Diabetes Self-Care Activities, and self-reported medication adherence. RESULTS:--Of the patients, 19% met the criteria for probable major depression (HANDS score >=9), and an additional 66.5% reported at least some depressive symptoms. After controlling for covariates, patients with probable major depression reported significantly fewer days' adherent to diet, exercise, and glucose self-monitoring regimens (P < 0.01) and 2.3-fold increased odds of missing medication doses in the previous week (95% CI 1.5-3.6, P < 0.001) compared with all other respondents. Continuous depressive symptom severity scores were better predictors of nonadherence to diet, exercise, and medications than categorically defined probable major depression. Major depression was a better predictor of glucose monitoring. Among the two-thirds of patients not meeting the criteria for major depression (HANDS score <9, n = 709), increasing HANDS scores were incrementally associated with poorer self-care behaviors (P < 0.01). CONCLUSIONS:--These findings challenge the conceptualization of depression as a categorical risk factor for nonadherence and suggest that even low levels of depressive symptomatology are associated with nonadherence to important aspects of diabetes self-care. Interventions aimed at alleviating depressive symptoms, which are quite common, could result in significant improvements in diabetes self-care.

Clear cell renal cell carcinomas (ccRCCs) epitomize the most formidable clinical subtype among renal neoplasms. While the impact of tumor-associated fibroblasts on ccRCC progression is duly acknowledged, a paucity of literature exists elucidating the intricate mechanisms and signaling pathways operative at the individual cellular level. Employing single-cell transcriptomic analysis, we meticulously curated UMAP profiles spanning substantial ccRCC populations, delving into the composition and intrinsic signaling pathways of these cohorts. Additionally, Myofibroblasts were fastidiously categorized into discrete subpopulations, with a thorough elucidation of the temporal trajectory relationships between these subpopulations. We further probed the cellular interaction pathways connecting pivotal subpopulations with tumors. Our endeavor also encompassed the identification of prognostic genes associated with these subpopulations through Bulk RNA-seq, subsequently validated through empirical experimentation. A notable escalation in the nFeature and nCount of Myofibroblasts and EPCs within ccRCCs was observed, notably enriched in oxidation-related pathways. This phenomenon is postulated to be closely associated with the heightened metabolic activities of Myofibroblasts and EPCs. The Myofibroblasts subpopulation, denoted as C3 HMGA1+ Myofibroblasts, emerges as a pivotal subset, displaying low differentiation and positioning itself at the terminal point of the temporal trajectory. Intriguingly, these cells exhibit a high degree of interaction with tumor cells through the MPZ signaling pathway network, suggesting that Myofibroblasts may facilitate tumor progression via this pathway. Prognostic genes associated with C3 were identified, among which TUBB3 is implicated in potential resistance to tumor recurrence. Finally, experimental validation revealed that the knockout of the key gene within the MPZ pathway, MPZL1, can inhibit tumor activity, proliferation, invasion, and migration capabilities. This investigation delves into the intricate mechanisms and interaction pathways between Myofibroblasts and ccRCCs at the single-cell level. We propose that targeting MPZL1 and the oxidative phosphorylation pathway could serve as potential key targets for treating the progression and recurrence of ccRCC. This discovery paves the way for new directions in the treatment and prognosis diagnosis of ccRCC in the future.