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Biology of Blood and Marrow... Dec 2020Ruxolitinib is an oral JAK1/2 inhibitor that is approved for use in patients with intermediate and high-risk myelofibrosis (MF) based on its proven spleen and symptom... (Review)
Review
Ruxolitinib is an oral JAK1/2 inhibitor that is approved for use in patients with intermediate and high-risk myelofibrosis (MF) based on its proven spleen and symptom burden reduction. Its impact on hematopoietic stem cell transplantation (HSCT) outcomes is largely unknown, however. A significant number of patients proceeding to HSCT have been treated with ruxolitinib, and the specifics of its peritransplantation use vary widely in the published literature. Here we review the currently published data and experience to guide management of patients with MF on ruxolitinib proceeding to HSCT.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Nitriles; Primary Myelofibrosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines
PubMed: 32818555
DOI: 10.1016/j.bbmt.2020.08.015 -
Molecular Cancer Therapeutics Nov 2021Limited clinical data are available regarding the utility of multikinase inhibition in neuroblastoma. Repotrectinib (TPX-0005) is a multikinase inhibitor that targets...
Limited clinical data are available regarding the utility of multikinase inhibition in neuroblastoma. Repotrectinib (TPX-0005) is a multikinase inhibitor that targets ALK, TRK, JAK2/STAT, and Src/FAK, which have all been implicated in the pathogenesis of neuroblastoma. We evaluated the preclinical activity of repotrectinib monotherapy and in combination with chemotherapy as a potential therapeutic approach for relapsed/refractory neuroblastoma. sensitivity to repotrectinib, ensartinib, and cytotoxic chemotherapy was evaluated in neuroblastoma cell lines. antitumor effect of repotrectinib monotherapy, and in combination with chemotherapy, was evaluated using a genotypically diverse cohort of patient-derived xenograft (PDX) models of neuroblastoma. Repotrectinib had comparable cytotoxic activity across cell lines irrespective of mutational status. Combination with chemotherapy demonstrated increased antiproliferative activity across several cell lines. Repotrectinib monotherapy had notable antitumor activity and prolonged event-free survival compared with vehicle and ensartinib in PDX models ( < 0.05). Repotrectinib plus chemotherapy was superior to chemotherapy alone in -mutant and wild-type PDX models. These results demonstrate that repotrectinib has antitumor activity in genotypically diverse neuroblastoma models, and that combination of a multikinase inhibitor with chemotherapy may be a promising treatment paradigm for translation to the clinic.
Topics: Animals; Humans; Macrocyclic Compounds; Mice; Neuroblastoma; Pyrazoles
PubMed: 34482287
DOI: 10.1158/1535-7163.MCT-21-0126 -
Angewandte Chemie (International Ed. in... Sep 2021We report the first enantioselective addition of pyrazoles to 1,3-dienes. Secondary and tertiary allylic pyrazoles can be generated with excellent regioselectivity....
We report the first enantioselective addition of pyrazoles to 1,3-dienes. Secondary and tertiary allylic pyrazoles can be generated with excellent regioselectivity. Mechanistic studies support a pathway distinct from previous hydroaminations: a Pd -catalyzed ligand-to-ligand hydrogen transfer (LLHT). This hydroamination tolerates a range of functional groups and advances the field of diene hydrofunctionalization.
Topics: Alkadienes; Catalysis; Ligands; Molecular Structure; Palladium; Pyrazoles; Stereoisomerism
PubMed: 34145705
DOI: 10.1002/anie.202105679 -
Acta Haematologica 2021
Topics: COVID-19; Hematologic Neoplasms; Humans; Nitriles; Pyrazoles; Pyrimidines; SARS-CoV-2
PubMed: 32818929
DOI: 10.1159/000510770 -
ESMO Open 2019fusions are found at low frequencies (commonly <1%) in a range of common tumour types and at high frequencies (up to or greater than 90%) in rare cancer types... (Review)
Review
fusions are found at low frequencies (commonly <1%) in a range of common tumour types and at high frequencies (up to or greater than 90%) in rare cancer types (secretory breast carcinoma, mammary analogue secretory carcinoma and infantile fibrosarcoma). The fusions typically occur in a mutually exclusive fashion with other strong mitogenic drivers, and it is of significant importance to identify patients in order to offer transformative treatment with TRK inhibitors. Larotractinib or entrectinib have resulted in fast and durable response with few and reversible adverse events. Even though on-target resistance may occur, second generation TRK inhibitors are in development and have shown promising activity. Diagnostic strategies must be applied, considering available assays and specific tumour types.
Topics: Benzamides; Biomarkers, Tumor; Gene Fusion; Genetic Testing; Humans; Indazoles; Neoplasms; Patient Selection; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, Nerve Growth Factor; Time Factors; Treatment Outcome
PubMed: 31803506
DOI: 10.1136/esmoopen-2019-000612 -
Hematology. American Society of... Dec 2021The treatment of acute graft-versus-host disease (aGVHD) has become more nuanced in recent years with the development of improved risk classification systems and a... (Review)
Review
The treatment of acute graft-versus-host disease (aGVHD) has become more nuanced in recent years with the development of improved risk classification systems and a better understanding of its complex, multisystem pathophysiology. We review contemporary approaches to the risk stratification and initial treatment of aGVHD, including ongoing clinical trials. We summarize the findings that led to the first US Food and Drug Administration approval for steroid-refractory aGVHD (SR-aGVHD), ruxolitinib, as well as some of the challenges clinicians still face in treating SR-aGVHD. Finally, we discuss the evaluation and management of steroid-dependent aGVHD, which affects approximately one-third of patients who have long-term, waxing and waning symptoms distinct from chronic GVHD. Future clinical trials for aGVHD treatment may identify steroid-sparing approaches for patients who have a high likelihood of response and approaches to improve tissue repair and dysbiosis for those unlikely to respond to immunosuppression alone.
Topics: Acute Disease; Disease Management; Graft vs Host Disease; Humans; Male; Middle Aged; Nitriles; Pyrazoles; Pyrimidines; Steroids
PubMed: 34889409
DOI: 10.1182/hematology.2021000300 -
Nature Medicine Dec 2021Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (...
Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study ( NCT02561988 ) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30-400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 10/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.
Topics: Adult; Aged; Aged, 80 and over; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Female; Humans; Male; Mastocytosis, Systemic; Middle Aged; Pyrazoles; Pyrroles; Triazines
PubMed: 34873347
DOI: 10.1038/s41591-021-01538-9 -
Molecules (Basel, Switzerland) Dec 2020The pyrazole nucleus and its reduced forms, pyrazolines and pyrazolidine, are privileged scaffolds in medicinal chemistry due to their remarkable biological activities.... (Review)
Review
The pyrazole nucleus and its reduced forms, pyrazolines and pyrazolidine, are privileged scaffolds in medicinal chemistry due to their remarkable biological activities. A huge number of pyrazole derivatives have been studied and reported over time. This review article gives an overview of pyrazole derivatives that contain a styryl (2-arylvinyl) group linked in different positions of the pyrazole backbone. Although there are studies on the synthesis of styrylpyrazoles dating back to the 1970s and even earlier, this type of compound has rarely been studied. This timely review intends to summarize the properties, biological activity, methods of synthesis and transformation of styrylpyrazoles; thus, highlighting the interest and huge potential for application of this kind of compound.
Topics: Animals; Humans; Molecular Structure; Pyrazoles
PubMed: 33322752
DOI: 10.3390/molecules25245886 -
Microbiological Research Jan 2023Fipronil is a phenylpyrazole insecticide used in various agricultural, horticulture, and veterinary practices. Besides its wide range of applications, it also causes... (Review)
Review
Fipronil is a phenylpyrazole insecticide used in various agricultural, horticulture, and veterinary practices. Besides its wide range of applications, it also causes severe health hazards to the non-targeted organisms especially in developing countries. Fipronil showed hepatotoxic, nephrotoxic, neurotoxic, and altered reproductive development and endocrine system in humans and animals. Several methods have been already introduced for the removal of toxic fipronil including physicochemical and by the implementation of microorganisms. The microbial methods of fipronil degradation are the most promising and environmentally sustainable. The remediation of fipronil from the environment is an emerging task due to its enhanced residual concentration. Herein, we discuss the bioremediation potential of microbial strains in contaminated soil and water. It is shown that fipronil can be remediated from the environment using combined ecotechnologies. This review discusses the toxicity, different physico-chemical and biological methods, and sustainable developments in fipronil-contaminated agriculture and aquatic environments.
Topics: Animals; Humans; Biodegradation, Environmental; Pyrazoles; Agriculture; Insecticides
PubMed: 36403315
DOI: 10.1016/j.micres.2022.127247 -
Molecules (Basel, Switzerland) Jul 2020Nitrated-pyrazole-based energetic compounds have attracted wide publicity in the field of energetic materials (EMs) due to their high heat of formation, high density,... (Review)
Review
Nitrated-pyrazole-based energetic compounds have attracted wide publicity in the field of energetic materials (EMs) due to their high heat of formation, high density, tailored thermal stability, and detonation performance. Many nitrated-pyrazole-based energetic compounds have been developed to meet the increasing demands of high power, low sensitivity, and eco-friendly environment, and they have good applications in explosives, propellants, and pyrotechnics. Continuous and growing efforts have been committed to promote the rapid development of nitrated-pyrazole-based EMs in the last decade, especially through large amounts of Chinese research. Some of the ultimate aims of nitrated-pyrazole-based materials are to develop potential candidates of castable explosives, explore novel insensitive high energy materials, search for low cost synthesis strategies, high efficiency, and green environmental protection, and further widen the applications of EMs. This review article aims to present the recent processes in the synthesis and physical and explosive performances of the nitrated-pyrazole-based Ems, including monopyrazoles with nitro, bispyrazoles with nitro, nitropyrazolo[4,3-]pyrazoles, and their derivatives, and to comb the development trend of these compounds. This review intends to prompt fresh concepts for designing prominent high-performance nitropyrazole-based EMs.
Topics: Explosive Agents; Nitrates; Nitro Compounds; Pyrazoles; Thermodynamics
PubMed: 32751631
DOI: 10.3390/molecules25153475