ABSTRACT
Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Colorectal Neoplasms/drug therapy , Pyrroles/pharmacology , Thiazoles/pharmacology , Tumor Suppressor Protein p53/genetics , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/pharmacology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Doxorubicin/pharmacology , Drug Discovery , Drug Synergism , Female , Fluorouracil/pharmacology , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Mice , Mice, Nude , Protein Binding , Pyrroles/chemical synthesis , Thiazoles/chemical synthesis , Tumor Suppressor Protein p53/agonists , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor AssaysABSTRACT
HIV-1 RT is one of the most important antiviral targets in the treatment of acquired immunodeficiency syndrome (AIDS). Several crystallographic structures are available for this enzyme, mostly with bound inhibitors. Despite their importance for structure based drug design towards new anti-HIV retrovirals, the X-ray structures of the unliganded enzyme could only be obtained incomplete, with a low resolution and until recently even the conformation of the p66 thumb was controversial. In this work we have aligned different X-ray RT structures, and built up a computational model of RT using homology modeling, which was afterwards refined and validated through MD simulations with explicit solvent. The model enzyme was structurally stable through the whole MD simulation, showing a RMSD of 2 Angstrom from the starting geometry. The Ramanchandram plot has improved along the simulation. Both intra-domain and interdomain movements were observed. The thumb kept its closed conformation through the whole simulation. A contact map, hydration sites study and a detailed analysis of the solvation of the nucleotide binding site are also presented.
Subject(s)
HIV Reverse Transcriptase/chemistry , Models, Molecular , Binding Sites , HIV Reverse Transcriptase/metabolism , Hydrogen Bonding , Ligands , Nucleotides/chemistry , Nucleotides/metabolism , Protein Binding , Protein Structure, Tertiary , Protein Subunits/chemistry , Protein Subunits/metabolism , Solvents , WaterABSTRACT
New designs for Magnetic Resonance Imaging contrast agents are presented. Essentially, they all are host-guest inclusion complexes between y-cyclodextrins and polyazamacrocycles of gadolinium (III) ion. Substitutions have been made to the host to optimise the host-guest association. Molecular mechanics calculations have been performed, using the UFF force field for metals, to decide on the suitability of the substitutions, and to evaluate the host-guest energies of association. Interesting general conclusions have been obtained, concerning the improvement of Magnetic Resonance Imaging contrast agents; namely, a set of rational methodologies have been deduced to improve the association between the gadolinium (III) chelates and the cyclodextrins, and their efficiency is demonstrated with a large set of substituted complexes, opening new doors to increase the diagnostic capabilities of Magnetic Resonance Imaging.
