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The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment. Fibroblast growth factor receptor (FGFR) gene alterations are frequent findings in various rare and advanced cancers refractive to mainstay chemo-therapy or surgical interventions. Several FGFR inhibitors have been developed for addressing these genetically altered FGFR-harboring malignancies, and some have performed well in clinical trials. In contrast, others are still being investigated in different phases of clinical trials. FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. These include cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid malignancies. Pemigatinib is the only FGFR inhibitor globally approved (USA, EU, and Japan) and available as a targeted therapy for two types of cancer, including FGFR2 fusion or other rearrangements harboring cholangiocarcinoma and relapsed/refractory myeloid/lymphoid neoplasms with FGFR1 rearrangements. Myeloid/lymphoid neoplasm is the latest area of application added to the therapeutic armamentarium of FGFR inhibitors. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.

Background: Epilepsy is a neurological disorder characterized by anomalous brain activity, convulsions and odd behaviour. Ten pyrrole carbohydrate based analogues (Va-Vj) were synthesized with amide as intermediate in the current research with the goal of reducing convulsions and seizures. Materials and Methods: The newly developed compounds were synthesized. Numerous methods (IR, NMR, mass, elemental analysis, etc.,) were used to characterize these substances. Several models were used to test each of these molecules for anticonvulsant activity. By using the rotarod and ethanol potentiation techniques, neurotoxicity was also evaluated. The study meticulously examined each parameter and showed ADME predictions for each of the 10 congeners that were produced. In addition, studies on molecular docking employed the GABA-A target protein. Results: Anticonvulsant screening results identified compounds Ve, Vd, Vc and Va as the most efficacious of the series. All synthesized equivalents largely passed the neurotoxicity test. The results of molecular docking revealed significant interactions at the active site of GABA-A with Ile C:242, Asp C:424, Phe D:307, Arg C:250 Trp C:241 and Phe C:240 and the outcomes were good and in agreement with in vivo findings. Conclusion: The study's findings showed that some substances had promising anticonvulsant properties that were comparable to those of the standard drug. The highly active novel anticonvulsant analogues may therefore represent a possible lead and additional studies may result in a potential new drug candidate. [ABSTRACT FROM AUTHOR]

Graphene, owing to its unique chemical structure and extraordinary chemical, electrical, thermal, optical, and mechanical properties, has opened up a new vista of applications, specifically as novel sensing platforms. The last decade has seen an extensive exploration of graphene and graphene-based materials either alone or modified with nanoparticles and polymers for the fabrication of nanoscale biosensors. These biosensors displayed excellent conductivity, high sensitivity, and selectivity, good accuracy, and precision, rapid detection with low detection limits as well as long-term stability. The unmatched properties of graphene and graphene-based materials have been applied for the detection of a number of chemical and biological molecules successfully for the diagnosis of a variety of diseases, pathogens, and biomarkers of the diseases. This review is aimed to cover the fabrication methods, functionalization techniques, and biomedical applications along with the recent advancements in the field of development of graphene-based biosensors. Recent clinical trials and patents as well as market trends and opportunities associated with graphene-based biosensors are also summarized. The application of graphene-based biosensors in the detection of SARS-CoV-2 causing COVID-19 is also reviewed.

Depending upon the metal coordination capacity and the binding sites of proteins, interaction between metal and proteins leads to a number of changes in the protein molecule which may include the change in conformation, unfolding, overall charge, and aggregation in some cases. In this study, Cu(ii) and Ag(i) metal ions were selected to investigate aggregation of bovine serum albumin (BSA) molecule upon interaction by measuring the size and charge of the aggregates using nano-Zetasizer instrument. Two concentrations of metal ions were made to interact with a specific concentration of BSA and the size and zeta potential of BSA aggregates were measured from 0 min upto 18 h. The Cu(ii) and Ag(i) metal ions showed almost similar behavior in inducing the BSA aggregation and the intensity of peak corresponding to the normal-sized protein decreased with time, whereas the peak corresponding to the protein aggregate increased. However, the effect on zeta potential of the aggregates was observed to be different with both metal ions. The aggregation of protein due to interaction of different metal ions is important to study as it gives insight to the pathogenesis of many neurological disorders and would result in developing effective ways to limit their exposure.

Incidences of drug-resistant tuberculosis have become common and are rising at an alarming rate. Aminoacyl t-RNA synthetase has been validated as a newer target against Mycobacterium tuberculosis. Leucyl t-RNA synthetase (LeuRS) is ubiquitously found in all organisms and regulates transcription, protein synthesis, mitochondrial RNA cleavage, and proofreading of matured t-RNA. Leucyl t-RNA synthetase promotes growth and development and is the key enzyme needed for biofilm formation in Mycobacterium. Inhibition of this enzyme could restrict the growth and development of the mycobacterial population. A database consisting of 2734 drug-like molecules was screened against leucyl t-RNA synthetase enzymes through virtual screening. Based on the docking scores and MMGBSA energy values, the top three compounds were selected for molecular dynamics simulation. The druggable nature of the top three hits was confirmed by predicting their pharmacokinetic parameters. The top three hits—compounds 1035 (ZINC000001543916), 1054 (ZINC000001554197), and 2077 (ZINC000008214483)—were evaluated for their binding affinity toward leucyl t-RNA synthetase by an isothermal titration calorimetry study. The inhibitory activity of these compounds was tested against antimycobacterial activity, biofilm formation, and LeuRS gene expression potential. Compound 1054 (Macimorelin) was found to be the most potent molecule, with better antimycobacterial activity, enzyme binding affinity, and significant inhibition of biofilm formation, as well as inhibition of the LeuRS gene expression. Compound 1054, the top hit compound, has the potential to be used as a lead to develop successful leucyl t-RNA synthetase inhibitors. [ABSTRACT FROM AUTHOR]