Результаты поиска

Многоцелевые лекарственные препараты: новые 2025 и послерыночного контроля за безопасностью наркотиков, 2022-2024.

Полифармакология предназначена для развития соединений, действующих по крайней мере на two целевые показатели (многоцелевые лиганды, МТДЛ). В 2025, Европейское агентство по медицине (ЕМА), 38 наркотиков, и 11 из них были MTDL. Большинство из них - антитела-наркотики, биконкретные антитела или ингибиторы киназы, все из которых указаны для лечения опухолей, включая датопотамаб дерукстекан (гормон-позитивный рецептор, HER2-negative Рак молочной железы), тизотумаб ведотин (сокращенная шейная карцинома), линвосельтамб (четвёртая линия лечения множественной миеломы) и эрдафитиниб (сокращенная уротел

Drugging the efferocytosis process: concepts and opportunities.

The daily removal of billions of apoptotic cells in the human body via the process of efferocytosis is essential for homeostasis. To allow for this continuous efferocytosis, rapid phenotypic changes occur in the phagocytes enabling them to engulf and digest the apoptotic cargo. In addition, efferocytosis is actively anti-inflammatory and promotes resolution. Owing to its ubiquitous nature and the sheer volume of cell turnover, efferocytosis is a point of vulnerability. Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infe

Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact.

Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and/or genetic characteristics of HCC and their knowledge would clarify the optimal treatment approach in each patient. Several molecular mechanisms responsible for secondary resistance have been discovered over the last few years; they represent potential targets for new specific drugs. In this light, the advent of checkpoint inhibitors (ICIs) has been a new o

Совпадение в полном тексте источника
… Sphingosine kinase 2 (SphK2) and sphingosine-1-phosphate (S1P) determine regorafenib resistance through NF-kB activation in preclinical models of HCC [ 59 ], whilst low levels of secreted glycoprotein ADAMTSL5 restores regorafenib sensitivity [ 60 ]. …

Multiple Myeloma Cell-Derived Exosomes: Implications on Tumorigenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension between 50 nm and 100 nm in size that can be released by various cells and contribute to the pathogenesis and progression of MM. Exosomes enclose proteins, cytokines, lipids, microRNAs, long noncoding RNAs, and circular RNAs able to regulate interactions between MM plasma cells and adjacent cells. Throug

Medicinal chemistry perspectives on anticancer drug design based on clinical applications (2015-2025).

Cancer therapy has undergone a remarkable evolution over the past few decades, driven largely by innovations in medicinal chemistry. This review explores the pivotal role of medicinal chemistry in designing, optimizing, and classifying anticancer agents, from traditional cytotoxics to modern targeted therapies, immunotherapies, and radiotheranostics. The article categorizes FDA-approved anticancer drugs (2015-2025), evaluates their mechanisms of action, structural features, and structure-activity relationships (SAR), and highlights both success stories and challenges in clinical translation. A

Совпадение в полном тексте источника
… Metabolic/lipid pathway inhibitors Opaganib (ABC294640) Opaganib is a selective inhibitor of sphingosine kinase 2 (SK2), an enzyme that modulates inflammatory and oncogenic sphingolipid signaling. … Structure–activity relationship Opaganib (ABC294640) is a selective oral sphingosine kinase 2 (SK2) inhibitor that disrupts cancer-promoting S1P signaling. Its SAR centers on a lipophilic amide scaffold featuring a naphthyl group, which enhances SK2 selectivity and membrane permeability. …

Mechanisms of spinal glial activation in chemotherapy-induced peripheral neuropathy: Focus on microglia and astrocytes.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication in patients with malignant tumors during chemotherapy. The pathological mechanisms of CIPN remain unclear, and effective preventive and therapeutic strategies are still lacking, posing a major challenge in clinical practice. Aberrant activation of spinal glial cells, particularly microglia and astrocytes, is a key pathological hallmark of CIPN. Evidence from multiple animal models supports a causal link between glial activation and CIPN, suggesting that glial cells may serve as potential therapeutic targets. However, ow

Exosomes: A new option for osteoporosis treatment.

Osteoporosis is a systemic bone disease characterized by reduced bone mass and destruction of bone microarchitecture, leading to increased bone fragility and susceptibility to fracture. However, the pathogenesis and molecular mechanisms of this disease remain unclear. Extracellular vesicles, structures originating from the plasma membrane and ranging from 30 nm to 5 µm in diameter, play an important role in intercellular communication in the bone microenvironment. Exosomes are extracellular vesicles that deliver cargo molecules, including endogenous proteins, lipids and nucleic acids. These ca

Sexual dimorphism in cancer: molecular mechanisms and precision oncology perspectives.

Sex differences play a crucial role in determining tumor incidence, treatment sensitivity, and prognosis among men and women. However, current clinical cancer treatment strategies fail to account for these differences. Furthermore, the underlying mechanisms of tumor disparities between sexes remain elusive. Sex differences in sex chromosomes, hormone levels, metabolism, and immunity synergistically contribute to tumor-related disparities. As the demand for precision medicine escalates, there is an urgent need to conduct further exploration and research to address the tumor differences between

Extracellular Vesicles in Bone Metastasis: Key Players in the Tumor Microenvironment and Promising Therapeutic Targets.

Extracellular vesicles (EVs) are lipid membranous vesicles that are released from every type of cell. It has become clear that EVs are involved in a variety of biological phenomena, including cancer progression, and play critical roles in intracellular communication through the horizontal transfer of cellular cargoes such as proteins, DNA fragments, RNAs including mRNA and non-coding RNAs (microRNA, piRNA, and long non-coding RNA) and lipids. The most common cause of death associated with cancer is metastasis. Recent investigations have revealed that EVs are deeply associated with metastasis.

Bone Pain in Cancer Patients: Mechanisms and Current Treatment.

The skeletal system is the third most common site for cancer metastases, surpassed only by the lungs and liver. Many tumors, especially those of the breast, prostate, lungs, and kidneys, have a strong predilection to metastasize to bone, which causes pain, hypercalcemia, pathological skeletal fractures, compression of the spinal cord or other nervous structures, decreased mobility, and increased mortality. Metastatic cancer-induced bone pain (CIBP) is a type of chronic pain with unique and complex pathophysiology characterized by nociceptive and neuropathic components. Its treatment should be

Полиненасыщенные жирные добавки к кислоте в системе управления множественным склерозом: обзор анализа.

Полиинунасыщенные жирные кислоты (PUFA) уже давно исследованы в качестве потенциальной адъюнктурной терапии множественных склерозов из-за их иммуномодулятивных, антивоспалительных и нейрозащитных свойств. Вместе с тем имеющиеся данные по-прежнему являются разнородными и не были полностью картированы. Цель этого аналитического обзора заключалась в том, чтобы охарактеризовать данные о дополнении ПУФП, выявить тенденции в области исследований и пробелы в знаниях, а также придать контекстуальный характер результатам первичных исследований наряду с систематическими обзорами. Этот обзор был проведен

Review of COVID-19 Therapeutics by Mechanism: From Discovery to Approval.

The global research and pharmaceutical community rapidly mobilized to develop treatments for coronavirus disease 2019 (COVID-19). Existing treatments have been repurposed and new drugs have emerged. Here we summarize mechanisms and clinical trials of COVID-19 therapeutics approved or in development. Two reviewers, working independently, reviewed published data for approved COVID-19 vaccines and drugs, as well as developmental pipelines, using databases from the following organizations: United States Food and Drug Administration (US-FDA), European Medicines Agency (EMA), Japanese Pharmaceutical

Совпадение в полном тексте источника
… kinases 2 (SK2), dihydroceramide desaturase (DES1), and glucosylceramide (GCS) inhibitor | 2,3 | NCT04467840 (Completed) | July 20, 2021 | https://redhillbio.com/home/default.aspx | 150 Arakoda (tafenoquine) | 60 Degrees Pharmaceuticals | USA | Antiviral activity | TMPRSS2 inhibitor & viral protease … Octagam treatment was associated with improved functional status, Opaganib Opaganib is an oral sphingosine kinase 2 (SK2) inhibitor developed by RedHill Biopharma (Tel Aviv, Israel). Opaganib inhibits host SK2 but not viral SK2. …

Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions.

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Unders

Совпадение в полном тексте источника
… AC cleaves ceramides and allows for an increment in SP1 levels, which is also supported by an increment in SP1 biosynthesis by the sphingosine kinase enzyme, which is constitutively overexpressed in AML [ 156 , 157 ]. …

Anti-Angiogenic Activity of Drugs in Multiple Myeloma.

Angiogenesis represents a pivotal hallmark of multiple myeloma (MM) that correlates to patients' prognosis, overall survival, and drug resistance. Hence, several anti-angiogenic drugs that directly target angiogenic cytokines (i.e., monoclonal antibodies, recombinant molecules) or their cognate receptors (i.e., tyrosine kinase inhibitors) have been developed. Additionally, many standard antimyeloma drugs currently used in clinical practice (i.e., immunomodulatory drugs, bisphosphonates, proteasome inhibitors, alkylating agents, glucocorticoids) show anti-angiogenic effects further supporting t

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021.

The second year of the COVID-19 pandemic had no adverse effect on the number of new drug approvals by the US Food and Drug Administration (FDA). Quite the contrary, with a total of 50 new drugs, 2021 belongs to the most successful FDA years. We assign these new drugs to one of three levels of innovation: (1) first drug against a condition ("first-in-indication"), (2) first drug using a novel molecular mechanism ("first-in-class"), and (3) "next-in-class", i.e., a drug using an already exploited molecular mechanism. We identify 21 first-in-class, 28 next-in-class, and only one first-in-indicati

Manipulating Macrophage/Microglia Polarization to Treat Glioblastoma or Multiple Sclerosis.

Macrophages and microglia are implicated in several diseases with divergent roles in physiopathology. This discrepancy can be explained by their capacity to endorse different polarization states. Theoretical extremes of these states are called M1 and M2. M1 are pro-inflammatory, microbicidal, and cytotoxic whereas M2 are anti-inflammatory, immunoregulatory cells in favor of tumor progression. In pathological states, these polarizations are dysregulated, thus restoring phenotypes could be an interesting treatment approach against diseases. In this review, we will focus on compounds targeting ma

Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia.

The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia (CML), greatly prolonged the life of CML patients, and improved their prognosis. However, TKI resistance is still a major problem with CML patients, reducing the efficacy of treatment and their quality of life. TKI resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent resistance. Now, the main clinical strategy addressing TKI resistance is to switch to newly developed TKIs. However, data have shown that these new drugs may cause serio

Совпадение в полном тексте источника
… For cell lines with BCR-ABL mutation, bortezomib can also effectively inhibit their proteasome activity and induce apoptosis. 175 Wang's team studied the effect of bortezomib in combination with sphingosine kinase 1 inhibitor SKI in CML cell lines. … Mechanism studies have found that increased apoptosis is related to the down-regulation of BCR-ABL and myeloid cell leukemia-1 and the significant decrease of sphingosine kinase 1 expression. 176 Another team's results focused on a combination of bortezomib and mitotic inhibitors, such as microtubule …

A Randomized Controlled Pilot Study Evaluating the Safety and Efficacy of Nifuroxazide in Patients with Ulcerative Colitis.

BACKGROUND: The therapeutic potential of nifuroxazide in colitis has been explored in several experimental studies of ulcerative colitis (UC). AIM: To evaluate the efficacy of nifuroxazide in patients with UC. METHODS: Fifty patients with mild to moderate UC were randomly assigned into two groups (n = 25 each). The placebo group received a placebo alongside mesalamine (1 g three times daily [t.i.d.]) for six months. The nifuroxazide group received nifuroxazide (200 mg twice daily) in combination with mesalamine (1 g t.i.d). A gastroenterologist assessed disease severity using the partial May

Совпадение в полном тексте источника
… Metformin alleviates inflammation in oxazolone induced ulcerative colitis in rats: plausible role of sphingosine kinase 1/sphingosine 1 phosphate signaling pathway. Immuno Immunotoxicol . 2021;43(2):192–202. doi: 10.1080/08923973.2021.1878214 45. Karagozian R, Burakoff R. …

Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice.

Chemotherapy is frequently accompanied by several side effects, including nausea, diarrhea, anorexia and fatigue. Evidence from ours and other groups suggests that chemotherapy can also play a major role in causing not only cachexia, but also bone loss. This complicates prognosis and survival among cancer patients, affects quality of life, and can increase morbidity and mortality rates. Recent findings suggest that soluble factors released from resorbing bone directly contribute to loss of muscle mass and function secondary to metastatic cancer. However, it remains unknown whether similar mech

Immune mediated support of metastasis: Implication for bone invasion.

Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we describe

Совпадение в полном тексте источника
… A previous study suggested that CST6 can stabilize sphingosine kinase 1 (SPHK1) by inhibiting the activity of CTSB, whereas SPHK1 inhibits osteoclast formation through p38. Current evidence suggests that CST6 expression is significantly reduced in tumor cells [ 83 , 84 ]. … kinase 1. …