Small Molecules For Treatment Research Articles

Long term follow-up of refractory/relapsed hairy cell leukaemia patients treated with low-dose vemurafenib between 2013 and 2022 at the Department of Internal Medicine and Oncology, Semmelweis University.

Introduction: Hairy cell leukemia (HCL) is an indolent B-cell lymphoproliferative disease. BRAF V600E mutation is detected in nearly all classical HCL cases which offers the possibility of targeted therapy. Objective: The aim of our study was to assess the efficacy of low-dose vemurafenib as well as to assess the long term outcome of HCL patients treated with this drug at the Department of Internal Medicine and Oncology at Semmelweis University. Methods: We report on 10 patients with classical HCL treated with low-dose vemurafenib at our Department between 2013 and 2022. Results: As a result of fixed time low-dose vemurafenib treatment, 5 of 10 patients (5/10) achieved partial remission, 4 (4/10) had stable disease, and 1 (1/10) had MRD positivity. No patients achieved complete remission. The median progression-free survival was 28.5months while the overall survival was 82months. Conclusion: We confirm that low dose of vemurafenib is effective and safe in the vast majority of patients with HCL. This small-molecule oral treatment allows to gain valuable time-months or even years-before further, usually parenteral treatment options have to be given or before previous treatment has to be repeated. There are also promising data supporting the combination of vemurafenib with other drugs for the treatment of HCL patients which could provide even further possibility to bridge treatment.

Risk of Cancer Recurrence in Patients With Immune-Mediated Diseases With Use of Immunosuppressive Therapies: An Updated Systematic Review and Meta-Analysis

There are limited data on the safety of immunosuppressive therapy use in individuals with immune-mediated diseases with a history of malignancy, particularly with newer biologic and small-molecule treatments. We performed a systematic search of PubMed and Embase databases to identify studies examining the impact of immunosuppressive therapies on cancer recurrence across several immune-mediated diseases. Studies were pooled together using random-effects meta-analysis and stratified by type of treatment. Primary outcome was occurrence of incident cancers, defined as new or recurrent. Our meta-analysis included 31 studies (17 inflammatory bowel disease, 14 rheumatoid arthritis, 2 psoriasis, and 1 ankylosing spondylitis) contributing 24,328 persons and 85,784 person-years (p-y) of follow-up evaluation. Rates of cancer recurrence were similar among individuals not on immunosuppression (IS) (1627 incident cancers, 43,765 p-y; 35 per 1000 p-y; 95% CI, 27-43), receiving an anti-tumor necrosis factor (571 incident cancers, 17,772 p-y; 32 per 1000 p-y; 95% CI, 25-38), immunomodulators (1104 incident cancers, 17,018 p-y; 46 per 1000 p-y; 95% CI, 31-61), combination immunosuppression (179 incident cancers, 2659 p-y; 56 per 1000 p-y; 95% CI, 31-81). Patients receiving ustekinumab (5 incident cancers, 213 p-y; 21 per 1000 p-y; 95% CI, 0-44) and vedolizumab (37 incident cancers, 1951 p-y; 16 per 1000 p-y; 95% CI, 5-26) had numerically lower rates of cancer. There were no studies on Janus kinase inhibitors. Stratification of studies by timing of immunosuppression initiation did not reveal a medication effect based on early (<5 years) or delayed treatment initiation. In patients with immune-mediated diseases and a history of malignancy, we observed similar rates of cancer recurrence in those on no immunosuppression compared with different immunosuppressive treatments.

Regenerative engineering of long bones using the small molecule forskolin

Bone grafting procedures have become increasingly common in the United States, with approximately 500,000 cases occurring each year at a societal cost exceeding $2.4 billion. Recombinant human bone morphogenetic proteins (rhBMPs) are therapeutic agents that have been widely used by orthopedic surgeons to stimulate bone tissue formation alone and when paired with biomaterials. However, significant limitations such as immunogenicity, high production cost, and ectopic bone growth from these therapies remain. Therefore, efforts have been made to discover and repurpose osteoinductive small-molecule therapeutics to promote bone regeneration. Previously, we have demonstrated that a single-dose treatment with the small-molecule forskolin for just 24 h induces osteogenic differentiation of rabbit bone marrow-derived stem cells invitro, while mitigating adverse side effects attributed with prolonged small-molecule treatment schemes. In this study, we engineered a composite fibrin-PLGA [poly(lactide-co-glycolide)]-sintered microsphere scaffold for the localized, short-term delivery of the osteoinductive small molecule, forskolin. Invitro characterization studies showed that forskolin released out of the fibrin gel within the first 24 h and retained its bioactivity toward osteogenic differentiation of bone marrow-derived stem cells. The forskolin-loaded fibrin-PLGA scaffold was also able to guide bone formation in a 3-mo rabbit radial critical-sized defect model comparable to recombinant human bone morphogenetic protein-2 (rhBMP-2) treatment, as demonstrated through histological and mechanical evaluation, with minimal systemic off-target side effects. Together, these results demonstrate the successful application of an innovative small-molecule treatment approach within long bone critical-sized defects.

A modified natural small molecule inhibits triple-negative breast cancer growth by interacting with Tubb3

BackgroundTriple-negative breast cancer (TNBC) is a malignant tumor without specific therapeutic targets and a poor prognosis. Chemotherapy is currently the first-line therapeutic option for TNBC. However, due to the heterogeneity of TNBC, not all of TNBC patients are responsive to chemotherapeutic agents. Therefore, the demand for new targeted agents is critical. β-tubulin isotype III (Tubb3) is a prognostic factor associated with cancer progression, including breast cancer, and targeting Tubb3 may lead to improve TNBC disease control. Shikonin, the active compound in the roots of Lithospermun erythrorhizon suppresses the growth of various types of tumors, and its efficacy can be improved by altering its chemical structure. PurposeIn this work, the anti-TNBC effect of a shikonin derivative (PMMB276) was investigated, and its mechanism was also investigated. Study Design/MethodsThis study combines flow cytometry, immunofluorescence staining, immunoblotting, immunoprecipitation, siRNA silencing, and the iTRAQ proteomics assay to analyze the inhibition potential of PMMB276 on TNBC. In vivo study was performed, Balb/c female murine models with or without the small molecule treatments. ResultsHerein, we screened 300 in-house synthesized analogs of shikonin against TNBC and identified a novel small molecule, PMMB276; it suppressed cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase, suggesting that it could have a tumor suppressive role in TNBC. Tubb3 was identified as the target of PMMB276 using proteomic and biological activity analyses. Meanwhile, PMMB276 regulated microtubule dynamics in vitro by inducing microtubule depolymerization and it could act as a tubulin stabilizer by a different process than that of paclitaxel. Moreover, suppressing or inhibiting Tubb3 with PMMB276 reduced the growth of breast cancer in an experimental mouse model, indicating that Tubb3 plays a significant role in TNBC progression. ConclusionThe findings support the therapeutic potential of PMMB276, a Tubb3 inhibitor, as a treatment for TNBC. Our findings might serve as a foundation for the utilization of shikonin and its derivatives in the development of anti-TNBC.

Computational approaches streamlining drug discovery.

Computer-aided drug discovery has been around for decades, although the past few years have seen a tectonic shift towards embracing computational technologies in both academia and pharma. This shift is largely defined by the flood of data on ligand properties and binding to therapeutic targets and their 3D structures, abundant computing capacities and the advent of on-demand virtual libraries of drug-like small molecules in their billions. Taking full advantage of these resources requires fast computational methods for effective ligand screening. This includes structure-based virtual screening of gigascale chemical spaces, further facilitated by fast iterative screening approaches. Highly synergistic are developments in deep learning predictions of ligand properties and target activities in lieu of receptor structure. Here we review recent advances in ligand discovery technologies, their potential for reshaping the whole process of drug discovery and development, as well as the challenges they encounter. We also discuss how the rapid identification of highly diverse, potent, target-selective and drug-like ligands to protein targets can democratize the drug discovery process, presenting new opportunities for the cost-effective development of safer and more effective small-molecule treatments.

GSK will license Scynexis antifungal

GSK is beefing up its infectious disease portfolio with an antifungal from Scynexis. For $90 million up front and possible milestone-based payments up to $503 million, the pharma giant will get the rights to commercialize and further develop Scynexis’s antifungal Brexafemme (ibrexafungerp). The small-molecule treatment is approved by the US Food and Drug Administration to treat vulvovaginal candidiasis (VVC) and to reduce the incidence of recurrent VVC. It’s the first and only oral antifungal approved for both indications, according to the firms. Notably, the companies say ibrexafungerp has also shown activity against Candida auris , which is currently spreading through US health-care facilities. C. auris has been responsible for severe illness in people who are hospitalized, and it is frequently resistant to multiple commonly used antifungals, the US Centers for Disease Control and Prevention says . Ibrexafungerp is also in Phase 3 trials to treat invasive candidiasis , which is

Comparison of Pronase versus Manual Dechorionation of Zebrafish Embryos for Small Molecule Treatments.

Zebrafish are a powerful animal model for small molecule screening. Small molecule treatments of zebrafish embryos usually require that the chorion, an acellular envelope enclosing the embryo, is removed in order for chemical compounds to access the embryo from the bath medium. For large-scale studies requiring hundreds of embryos, manual dechorionation, using forceps, can be a time-consuming and limiting process. Pronase is a non-specific protease that is widely used as an enzymatic alternative for dechorionating zebrafish embryos. However, whether pronase treatments alter the effects of subsequent small molecule treatments has not been addressed. Here, we provide a detailed protocol for large-scale pronase dechorionation of zebrafish embryos. We tested whether pronase treatment can influence the efficacy of drug treatments in zebrafish embryos. We used a zebrafish model for Duchenne muscular dystrophy (DMD) to investigate whether the efficacies of trichostatin-A (TSA) or salermide + oxamflatin, small molecule inhibitors known to ameliorate the zebrafish dmd muscle degeneration phenotype, are significantly altered when embryos are treated with pronase versus manual dechorionation. We also tested the effects of pronase on the ability of the anthracycline cancer drug doxorubicin to induce cardiotoxicity in zebrafish embryos. When comparing pronase- versus forceps-dechorionated embryos used in these small molecule treatments, we found no appreciable effects of pronase on animal survival or on the effects of the small molecules. The significant difference that was detected was a small improvement in the ability of salermide + oxamflatin to ameliorate the dmd phenotype in pronase-treated embryos when compared with manual dechorionation. Our study supports the use of pronase treatment as a dechorionation method for zebrafish drug screening experiments.

Interdependence of SS18-SSX-driven YAP1 and β-Catenin Activation in Synovial Sarcoma.

This study provides deeper insights into synovial sarcoma tumor biology demonstrating a mutual dependence between YAP1/TAZ and β-catenin transcriptional activity and a complex interplay with the SS18-SSX fusion protein within the BAF complex.

Neosuberitenone, a New Sesterterpenoid Carbon Skeleton; New Suberitenones; and Bioactivity against Respiratory Syncytial Virus, from the Antarctic Sponge Suberites sp.

Respiratory syncytial virus (RSV) is a highly contagious human pathogen that poses a significant threat to children under the age of two, and there is a current need for new small molecule treatments. The Antarctic sponge Suberites sp. is a known source of sesterterpenes, and following an NMR-guided fractionation procedure, it was found to produce several previously unreported metabolites. Neosuberitenone (1), with a new carbon scaffold herein termed the 'neosuberitane' backbone, six suberitenone derivatives (2-7), an ansellane-type terpenoid (8), and a highly degraded sesterterpene (9), as well as previously reported suberitenones A (10) and B (11), were characterized. The structures of all of the isolated metabolites including absolute configurations are proposed on the basis of NMR, HRESIMS, optical rotation, and XRD data. The biological activities of the metabolites were evaluated in a range of infectious disease assays. Suberitenones A, B, and F (3) were found to be active against RSV, though, along with other Suberites sp. metabolites, they were inactive in bacterial and fungal screens. None of the metabolites were cytotoxic for J774 macrophages or A549 adenocarcinoma cells. The selectivity of suberitenones A, B, and F for RSV among other infectious agents is noteworthy.

Structure-Based Design of Glycosylated Oxytocin Analogues with Improved Selectivity and Antinociceptive Activity.

Acute and chronic pain is often treated with opioids despite the negative side effects of constipation, physical dependence, respiratory depression, and overdose. The misuse of opioid analgesics has given rise to the opioid crisis/epidemic, and alternate nonaddictive analgesics are urgently needed. Oxytocin, a pituitary hormone, is an alternative to the small molecule treatments available and has been used as an analgesic as well as for the treatment and prevention of opioid use disorder (OUD). Clinical implementation is limited by its poor pharmacokinetic profile, a result of the labile disulfide bond between two cysteine residues in the native sequence. Stable brain penetrant oxytocin analogues have been synthesized by replacement of the disulfide bond with a stable lactam and glycosidation of the C-terminus. These analogues show exquisite selectivity for the oxytocin receptor and potent in vivo antinociception in mice following peripheral (i.v.) administration, supporting further study of their clinical potential.

Net Remission Rates with Biologic and Small Molecule Treatment in Ulcerative Colitis: A Reappraisal of the Clinical Trial Data

Net Remission Rates with Biologic and Small Molecule Treatment in Ulcerative Colitis: A Reappraisal of the Clinical Trial Data

Tumor-suppressive disruption of cancer subtype-associated super enhancer circuits by small molecule treatment.

Transcriptional cancer subtypes which correlate with traits such as tumor growth, drug sensitivity or the chances of relapse and metastasis, have been described for several malignancies. The core regulatory circuits (CRCs) defining these subtypes are established by chromatin super enhancers (SEs) driving key transcription factors (TFs) specific for the particular cell state. In neuroblastoma (NB), one of the most frequent solid pediatric cancer entities, two major SE-directed molecular subtypes have been described: A more lineage-committed adrenergic (ADRN) and a mesenchymal (MES) subtype. Here, we found that a small isoxazole molecule (ISX), a frequently used pro-neural drug, reprogrammed SE activity and switched NB cells from an ADRN subtype towards a growth-retarded MES-like state. The MES-like state shared strong transcriptional overlap with ganglioneuroma (GN), a benign and highly differentiated tumor of the neural crest. Mechanistically, ISX suppressed chromatin binding of N-MYC, a CRC-amplifying transcription factor, resulting in loss of key ADRN subtype-enriched components such as N-MYC itself, PHOX2B and ALK, while concomitently, MES subtype markers were induced. Globally, ISX treatment installed a chromatin accessibility landscape typically associated with low risk NB. In summary, we provide evidence that CRCs and cancer subtype reprogramming might be amenable to future therapeutic targeting.

An update on brown adipose tissue and obesity intervention: Function, regulation and therapeutic implications.

Overweight and obesity have become a world-wide problem. However, effective intervention approaches are limited. Brown adipose tissue, which helps maintain body temperature and contributes to thermogenesis, is dependent on uncoupling protein1. Over the last decade, an in-creasing number of studies have found that activating brown adipose tissue and browning of white adipose tissue can protect against obesity and obesity-related metabolic disease. Brown adipose tissue has gradually become an appealing therapeutic target for the prevention and re-versal of obesity. However, some important issues remain unresolved. It is not certain whether increasing brown adipose tissue activity is the cause or effect of body weight loss or what the risks might be for sympathetic nervous system-dependent non-shivering thermogenesis. In this review, we comprehensively summarize approaches to activating brown adipose tissue and/or browning white adipose tissue, such as cold exposure, exercise, and small-molecule treatment. We highlight the functional mechanisms of small-molecule treatment and brown adipose tissue transplantation using batokine, sympathetic nervous system and/or gut microbiome. Finally, we discuss the causality between body weight loss induced by bariatric surgery, exercise, and brown adipose tissue activity.

A hydrogen-deuterium exchange mass spectrometry-based protocol for protein-small molecule interaction analysis.

Protein-small molecule interaction is vital in regulating protein functions and controlling various cellular processes. Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful methodology to study protein-small molecule interactions, however, to accurately probe the conformational dynamics of the protein upon small molecule binding, the HDX-MS experimental conditions should be carefully controlled and optimized. Here, we present the detailed continuous-labeling, bottom-up HDX-MS protocol for studying protein-small molecule interactions. We took a side-by-side HDX kinetics comparison of the Hsp90N protein with or without the treatment of small molecules (i.e., Radicicol, Geldanamycin) for displaying conformational changes induced by molecular interactions between Hsp90N and small molecules. Our sensitive and robust experimental protocol can facilitate the novice to quickly carry out the structural characterization of protein-small molecule interactions.

Modified mRNA Therapeutics for Heart Diseases.

Cardiovascular diseases (CVD) remain a substantial global health problem and the leading cause of death worldwide. Although many conventional small-molecule treatments are available to support the cardiac function of the patient with CVD, they are not effective as a cure. Among potential targets for gene therapy are severe cardiac and peripheral ischemia, heart failure, vein graft failure, and some forms of dyslipidemias. In the last three decades, multiple gene therapy tools have been used for heart diseases caused by proteins, plasmids, adenovirus, and adeno-associated viruses (AAV), but these remain as unmet clinical needs. These gene therapy methods are ineffective due to poor and uncontrolled gene expression, low stability, immunogenicity, and transfection efficiency. The synthetic modified mRNA (modRNA) presents a novel gene therapy approach which provides a transient, stable, safe, non-immunogenic, controlled mRNA delivery to the heart tissue without any risk of genomic integration, and achieves a therapeutic effect in different organs, including the heart. The mRNA translation starts in minutes, and remains stable for 8-10 days (pulse-like kinetics). The pulse-like expression of modRNA in the heart induces cardiac repair, cardiomyocyte proliferation and survival, and inhibits cardiomyocyte apoptosis post-myocardial infarction (MI). Cell-specific (cardiomyocyte) modRNA translation developments established cell-specific modRNA therapeutics for heart diseases. With these laudable characteristics, combined with its expression kinetics in the heart, modRNA has become an attractive therapeutic for the treatment of CVD. This review discusses new developments in modRNA therapy for heart diseases.

IN‐VIVO EVALUATION OF APN‐1808, A TAU SMALL MOLECULE THERAPEUTIC

AbstractBackgroundThe high value for Alzheimer’s Disease and other taupathies of a small molecule treatment that can alter disease course is widely acknowledged. We aim to investigate such a therapeutic by leveraging our small molecule CNS aggregated protein discovery platform.MethodOur small molecule discovery platform consists of our proprietary small molecule collection, unique PET imaging biomarkers and cryoEM structures. Our proprietary collection of CNS‐focused aggregated protein binding agents, previously developed by APRINOIA to map the structure‐activity relationship of its tau PET tracer programs, was screened for tau binding and further interrogated for other desirable properties such as selectivity and oral availability. Further efforts derived guidance from the cryoEM structure of our lead compound bound to Tau aggregates. These efforts resulted in our small molecule lead compound APN‐1808.Using rTg4510 mice, which over express 4R tau, we first investigated dose‐response by using in‐vivo PET imaging to measure percent occupancy of APN‐1808. Upon selecting an appropriate dose range, we engaged in 90 day, twice a day dosing of APN‐1808 in rTg4510 mice.ResultMice dosed with APN‐1808 showed improvements both biochemically and phenotypically over vehicle controls. Improvements included increase in synaptic protein level, reduction in overall tau burden, reduction in weight loss and other behavioral observations.ConclusionSeveral readouts showed improvement in the dosed groups compared to controls, including increase of synapse level, reduction of weight loss and reduction of total tau. Further investigations are ongoing.

Curative Measures for Cystic Fibrosis: A Perspective on Current Stem Cell–Based, Gene, and Small Molecule Therapies

Cystic fibrosis (CF), which is caused by a defect or deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, continues to be a life-limiting multiorgan disease with severe phenotypic manifestations in affected patients. Current approaches to CF therapy have advanced far beyond symptomatic treatment, targeting the aberrant CFTR for therapeutic results. Novel small molecule treatments, or CF modulators, were the first to significantly improve the quality of life for patients with CF. These low-molecular-weight drugs can easily traverse the cell membrane and effect transcriptive changes in cells, albeit only for those with the specific mutations addressed by the drugs. However, other stem cell–based treatments, such as mesenchymal stromal cell therapy or induced pluripotent stem cell therapy, and gene therapies, such as CRISPR/Cas9 and viral vectors, are being researched as potential mutation-independent cures. These therapies have yet to progress to clinical trials, but their efficacies in various CF models prove their promise as future treatment options and potential cures. In this review, 3 potential contemporary therapies for CF and their current statuses and trajectories as clinical tools are discussed.

595 Anticodon engineered transfer ibonucleic acid and small-molecule combination treatment of cystic fibrosis nonsense mutations

595 Anticodon engineered transfer ibonucleic acid and small-molecule combination treatment of cystic fibrosis nonsense mutations

Different methods in COVID-19 treatments

COVID-19 is a global pandemic starting from China in late 2019 and spread over the world dramatically rapid. A lot of methods were tried by experts to find treatments of COVID-19. Compared with COVID-19, not only the death rate but also spread rate is lower, as well as its existing time. It is also possible that transmitted the virus through eyes, noses and ears. Vaccination has been used as precaution treatment. And some small molecules are used to treat patients who have positive results in severe situation. Adults and pediatric patients who infect COVID-19 pandemic in mild to moderate situation, can use small molecule treatments in emergency only. However, vaccination is unable to protect people 100% and small molecules, such as paxlovid, have not been approved, but have been authorized for emergency use by Food and Drug Administration (FDA). This review focused on methods and mechanism of different treatments of COVID-19.

MetaProClust-MS1: an MS1 Profiling Approach for Large-Scale Microbiome Screening.

ABSTRACTMetaproteomics is used to explore the functional dynamics of microbial communities. However, acquiring metaproteomic data by tandem mass spectrometry (MS/MS) is time-consuming and resource-intensive, and there is a demand for computational methods that can be used to reduce these resource requirements. We present MetaProClust-MS1, a computational framework for microbiome feature screening developed to prioritize samples for follow-up MS/MS. In this proof-of-concept study, we tested and compared MetaProClust-MS1 results on gut microbiome data, from fecal samples, acquired using short 15-min MS1-only chromatographic gradients and MS1 spectra from longer 60-min gradients to MS/MS-acquired data. We found that MetaProClust-MS1 identified robust gut microbiome responses caused by xenobiotics with significantly correlated cluster topologies of comparable data sets. We also used MetaProClust-MS1 to reanalyze data from both a clinical MS/MS diagnostic study of pediatric patients with inflammatory bowel disease and an experiment evaluating the therapeutic effects of a small molecule on the brain tissue of Alzheimer’s disease mouse models. MetaProClust-MS1 clusters could distinguish between inflammatory bowel disease diagnoses (ulcerative colitis and Crohn’s disease) using samples from mucosal luminal interface samples and identified hippocampal proteome shifts of Alzheimer’s disease mouse models after small-molecule treatment. Therefore, we demonstrate that MetaProClust-MS1 can screen both microbiomes and single-species proteomes using only MS1 profiles, and our results suggest that this approach may be generalizable to any proteomics experiment. MetaProClust-MS1 may be especially useful for large-scale metaproteomic screening for the prioritization of samples for further metaproteomic characterization, using MS/MS, for instance, in addition to being a promising novel approach for clinical diagnostic screening.IMPORTANCE Growing evidence suggests that human gut microbiome composition and function are highly associated with health and disease. As such, high-throughput metaproteomic studies are becoming more common in gut microbiome research. However, using a conventional long liquid chromatography (LC)-MS/MS gradient metaproteomics approach as an initial screen in large-scale microbiome experiments can be slow and expensive. To combat this challenge, we introduce MetaProClust-MS1, a computational framework for microbiome screening using MS1-only profiles. In this proof-of-concept study, we show that MetaProClust-MS1 identifies clusters of gut microbiome treatments using MS1-only profiles similar to those identified using MS/MS. Our approach allows researchers to prioritize samples and treatments of interest for further metaproteomic analyses and may be generally applicable to any proteomic analysis. In particular, this approach may be especially useful for large-scale metaproteomic screening or in clinical settings where rapid diagnostic evidence is required.