Lymphomas are among the ten most common cancers, and, although progress has been achieved in increasing survival, there is still an unmet need for more effective therapeutic approaches, including better options for patients with refractory tumors that initially respond but then relapse. The lack of effective alternative treatment options highlights the need to develop new therapeutic strategies capable of improving survival prospects for lymphoma patients. Herein, we describe the identification and exploration of the SAR of a series of [1,2]oxazolo[5,4-e]isoindoles as potent small molecules that bind to the colchicine site of tubulin and that have promise for the treatment of refractory lymphomas. Exploration of the chemical space of this class of compounds at the pyrrole moiety and at the [1,2]oxazole ring highlighted two compounds bearing a 3,5-dimethoxybenzyl and a 3,4,5-trimethoxybenzyl group as potent candidates and showed that structural modifications at the isoxazole moiety are generally not favorable for activity. The two best candidates showed efficacy against different lymphoma histotypes and displayed 88 and 80% inhibition of colchicine binding fitting well into the colchicine pocket, as demonstrated by X-ray crystallography TR-TTL-complexes, docking and thermodynamic analysis of the tubulin-colchicine complex structure. These results were confirmed by transcriptome data, thus indicating [1,2]oxazolo[5,4-e]isoindoles are promising candidates as antitubulin agents for the treatment of refractory lymphomas.
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http://dx.doi.org/10.1016/j.ejmech.2022.114744 | DOI Listing |
Eur Thyroid J
January 2025
Z Qiu, Department of Nuclear Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Shanghai, 200233, China.
Objective: Pleural metastasis (PM) is rare in patients with differentiated thyroid cancer (DTC). Radioiodine (131I) therapy has been the main treatment for postoperative metastasis and recurrence of DTC. However, clinical data on PM from DTC are limited.
View Article and Find Full Text PDFPatients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes. Gemcitabine + oxaliplatin (GemOx) with rituximab, a standard salvage therapy, yields complete response (CR) rates of approximately 30% and median overall survival (OS) of 10-13 months. Patients with refractory disease fare worse, with a CR rate of 7% for subsequent therapies and median OS of 6 months.
View Article and Find Full Text PDFMedicine (Baltimore)
January 2025
Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia, Hohhot, China.
Rationale: The occurrence of refractory small cell lung cancer (rSCLC) with pancreatic metastasis is a relatively rare clinical condition, which is typically accompanied by a poor prognosis and rapid disease progression.
Patient Concerns: A 65-year-old male farmer from China was diagnosed with limited-stage small cell lung cancer (SCLC) 8 months ago. Following 6 cycles of EP chemotherapy, the patient's tumor response showed partial relief.
Am J Ther
January 2025
Northwell, New Hyde Park, NY, Department of Medicine, Manhasset, NY.
Background: C3 glomerulopathy (C3G) is a rare disease affecting the complement alternative pathway, categorized into dense deposit disease and C3 glomerulonephritis. Dense deposit disease predominantly affects younger individuals, while C3 glomerulonephritis tends to manifest in older populations. The diseases are characterized by dysregulation of the complement alternative pathway, leading to the deposition of complement components in the glomeruli and subsequent renal dysfunction.
View Article and Find Full Text PDFJ Child Adolesc Psychopharmacol
January 2025
Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Autism spectrum disorder (ASD) is characterized by deficits in social behavior and executive function (EF), particularly in cognitive flexibility. Whether transcranial magnetic stimulation (TMS) can improve cognitive outcomes in patients with ASD remains an open question. We examined the acute effects of prefrontal TMS on cortical excitability and fluid cognition in individuals with ASD who underwent TMS for refractory major depression.
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