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Advanced Science (Weinheim,... Sep 2023Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of...
Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl-XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib-induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl-XL. The intervention effect is dependent on the alleviation of the nilotinib-induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin-proteasome degradation of Bcl-XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl-XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.
Topics: Animals; Chloroquine; Endothelial Cells; Apoptosis; Pyrimidines; Ubiquitin-Specific Proteases
PubMed: 37452432
DOI: 10.1002/advs.202302002 -
Expert Opinion on Pharmacotherapy Apr 2024The introduction of the first JAK inhibitor (JAKi) ruxolitinib 10 years ago represented a pivotal advancement in myelofibrosis (MF) treatment, mostly in terms of... (Review)
Review
INTRODUCTION
The introduction of the first JAK inhibitor (JAKi) ruxolitinib 10 years ago represented a pivotal advancement in myelofibrosis (MF) treatment, mostly in terms of spleen and symptoms response. Nowadays three more JAKi, fedratinib, pacritinib, and momelotinib, are available for both ruxolitinib-resistant and naïve patients. Moreover, many drugs are currently being investigated, both alone and in combination with JAKi.
AREAS COVERED
In this review we discuss the long-term data of ruxolitinib and more recent evidence coming from clinical trials of fedratinib, pacritinib, and momelotinib, used as first- or second-line MF therapy. More, focus is set on data from non-JAKi drugs, such as the quite extensively studied BET-inhibitors (pelabresib) and BCL-inhibitors (navitoclax), novel target therapies, and drugs aimed to improve anemia, still representing a major determinant of reduced survival in MF.
EXPERT OPINION
It's now evident that JAKi monotherapy, though clinically effective, is rarely able to change MF natural history; novel drugs are promising but long-term data are inevitably lacking. We feel that soon MF treatment will require clinicians to select the most appropriate JAKi inhibitor, based on patient characteristics, associating either front-line or in case of early suboptimal response, non-JAKi drugs with the aim to pursue disease modification.
Topics: Humans; Primary Myelofibrosis; Janus Kinase Inhibitors; Nitriles; Pyrimidines; Animals; Molecular Targeted Therapy; Pyrazoles
PubMed: 38738513
DOI: 10.1080/14656566.2024.2354461 -
JACC. Heart Failure May 2024
Topics: Humans; Heart Failure; Hospitalization; Pyrimidines; Male; Heterocyclic Compounds, 2-Ring
PubMed: 38573267
DOI: 10.1016/j.jchf.2024.02.024 -
Journal of Clinical Oncology : Official... Feb 2024
Topics: Humans; Waldenstrom Macroglobulinemia; Piperidines; Pyrazoles; Pyrimidines
PubMed: 38048514
DOI: 10.1200/JCO.23.01881 -
JAMA Feb 2024
Topics: Humans; Benzenesulfonamides; Chronic Cough; Pyrimidines; Sulfonamides
PubMed: 38349378
DOI: 10.1001/jama.2023.26032 -
Mayo Clinic Proceedings Jan 2024
Topics: Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Protein Kinase Inhibitors
PubMed: 38176834
DOI: 10.1016/j.mayocp.2023.11.014 -
The Annals of Pharmacotherapy Aug 2023To review the pharmacokinetics, efficacy, and safety of topical ruxolitinib for treatment of nonsegmental vitiligo. (Review)
Review
OBJECTIVE
To review the pharmacokinetics, efficacy, and safety of topical ruxolitinib for treatment of nonsegmental vitiligo.
DATA SOURCES
Literature published between January 1983 and October 2022 was reviewed from MEDLINE and ClinicalTrials.gov.
STUDY SELECTION AND DATA EXTRACTION
Relevant articles in English and data from clinical trials were included.
DATA SYNTHESIS
In 2 phase II trials, treatment with ruxolitinib cream showed significant improvements in Vitiligo Area Scoring Index (VASI) scores compared with controls. The 1.5% concentration applied twice daily showed the best results after 52 weeks, with 50% VASI improvement in 58% of patients, 75% VASI improvement in 52% of patients, and 90% VASI improvement in 33% of patients. In 2 phase III trials, more patients achieved at least 75% improvement in facial VASI at 24 weeks (primary endpoint; trial 1: 29.9%, trial 2: 29.9%) than controls (trial 1: 7.5% [ < 0.0001], trial 2: 12.9% [ < 0.01]). Common adverse effects were erythema, pruritus, and acne; all events were mild.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS
This review summarizes the pharmacokinetics, efficacy, and safety data regarding topical ruxolitinib for vitiligo. Ruxolitinib is associated with significant clinical improvements with low bioavailability and minimal adverse effects compared with conventional topical steroids, calcineurin inhibitors, phototherapy, and depigmentation agents.
CONCLUSIONS
Ruxolitinib cream is the first therapy approved by the Food and Drug Administration for repigmentation of nonsegmental vitiligo. Clinicians should consider these benefits when recommending treatment as conventional therapies may be time-intensive and carry greater risks of adverse effects.
Topics: Humans; Vitiligo; Treatment Outcome; Nitriles; Pyrimidines; Drug-Related Side Effects and Adverse Reactions
PubMed: 36564903
DOI: 10.1177/10600280221143748 -
Journal of Medicinal Chemistry Feb 2024This Perspective is the eighth in an annual series that summarizes successful fragment-to-lead (F2L) case studies published each year. A tabulated summary of relevant... (Review)
Review
This Perspective is the eighth in an annual series that summarizes successful fragment-to-lead (F2L) case studies published each year. A tabulated summary of relevant articles published in 2022 is provided, and features such as target class, screening methods, and ligand efficiency are discussed both for the 2022 examples and for the combined examples over the years 2015-2022. In addition, trends and new developments in the field are summarized. In 2022, 18 publications described successful fragment-to-lead studies, including the development of three clinical compounds (MTRX1719, MK-8189, and BI-823911).
Topics: Drug Discovery; Chemistry, Pharmaceutical; Publications; Ligands; Pyrimidines; Sulfur Compounds
PubMed: 38289623
DOI: 10.1021/acs.jmedchem.3c02070 -
EBioMedicine Jul 2023Pyrimidine nucleotides fuel the growth of colorectal cancer (CRC), making their associated proteins potential targets for cancer intervention. Uridine-Cytidine Kinase...
BACKGROUND
Pyrimidine nucleotides fuel the growth of colorectal cancer (CRC), making their associated proteins potential targets for cancer intervention. Uridine-Cytidine Kinase Like-1(UCKL1) is an enzyme involved in the pyrimidine salvage pathway. It is highly expressed in multiple cancers. But the function and underlying mechanism of UCKL1 in CRC are yet to study.
METHODS
Large-scale genomic analysis was performed to search for potential CRC players related to pyrimidine metabolism. The function of UCKL1 in CRC were examined by RNA interference coupled with in vitro and in vivo assays. GSH/GSSG assay, NADP+ assay, ROS, and Lipid peroxidation assays were performed to check the function of UCKL1 in ferroptosis. Metabolomics analyses, RNA sequencing, western blotting, and rescue assays were done to reveal the underlying mechanisms of UCKL1. Xenograft mouse model was used to examine the therapeutic potential of UCKL1 as a target in combination with other ferroptosis inducers.
FINDINGS
UCKL1 was identified to repress ferroptosis in CRC cells. It was highly expressed in CRC. It regulated CRC cells proliferation and migration. Downregulation of UCKL1 led to enhanced tumour lipid peroxidation. Intriguingly, UCKL1 reduction-mediated ferroptosis was not related to its role in catalyzing uridine monophosphate (UMP) and cytidine monophosphate (CMP) synthesis. Instead, UCKL1 stabilized Nrf2, which in turn promoted the expression of SLC7A11, a classical repressor of ferroptosis. Moreover, downregulation of UCKL1 sensitized CRC cells to GPX4 inhibitors in vitro and in vivo.
INTERPRETATION
Our study demonstrates that UCKL1 plays a non-canonical role in repressing ferroptosis through a UCKL1-Nrf2-SLC7A11 axis in CRC cells. Combinatorial strategy in targeting ferroptosis by depletion of UCKL1 and application of GPX4 inhibitors may serve as a new effective method for CRC treatment.
FUNDING
This study was supported in part by fund from National Natural Science Foundation of China (Grant No. 31970674 to PY), by the Basic and Applied Basic Research Program of Guangdong Province (Grant No. 2023A1515030245 to KL), by the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), and by National Key Clinical Discipline.
Topics: Humans; Animals; Mice; NF-E2-Related Factor 2; Biological Assay; Cell Proliferation; Disease Models, Animal; Colorectal Neoplasms; Pyrimidines
PubMed: 37343364
DOI: 10.1016/j.ebiom.2023.104650 -
Targeted Oncology Jan 2024Pemigatinib (Pemazyre), a selective, potent, reversible, oral inhibitor of fibroblast growth factor receptor (FGFR) 1-3, has received conditional (in the EU) or... (Review)
Review
Pemigatinib (Pemazyre), a selective, potent, reversible, oral inhibitor of fibroblast growth factor receptor (FGFR) 1-3, has received conditional (in the EU) or accelerated (in the USA) approval for the treatment of adults with previously treated, unresectable locally-advanced or metastatic cholangiocarcinoma (CCA) with an FGFR2 gene fusion or rearrangement. Over the course of a single-arm, phase 2 study (FIGHT-202), just over a third of patients with pretreated, advanced CCA [almost exclusively intrahepatic CCA (iCCA)] harbouring an FGFR2 fusion or rearrangement who received pemigatinib once daily (2 weeks on, 1 week off) had an objective response; nearly half had stable disease. Median progression-free survival and overall survival at the time of the final analysis were 7.0 months and 17.5 months, respectively. Pemigatinib was generally well tolerated and had a manageable safety profile. The most common treatment-related adverse event, hyperphosphataemia, was exclusively grade 1-2 in severity and, similarly, observed ocular and nail toxicities were rarely grade ≥ 3 in severity. Pending confirmation of its clinical benefits in an ongoing cisplatin plus gemcitabine-controlled, phase 3 study (FIGHT-302), pemigatinib provides a valuable targeted therapy for pretreated patients with advanced (i)CCA harbouring a FGFR2 fusion or rearrangement.
Topics: Adult; Humans; Cholangiocarcinoma; Pyrimidines; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Morpholines; Pyrroles
PubMed: 38206555
DOI: 10.1007/s11523-023-01024-x