Cross-company collaboration to leverage analytics for clinical quality and accelerate drug development: The IMPALA industry group.

Quality functions from pharmaceutical sponsor companies aim to increase the use of analytics in their oversight of Good Clinical Practices and Pharmacovigilance activities. To leverage and accelerate progress, several companies decided to establish a collaborative model. The goals of this collaboration span the sharing of knowledge and ideas, the sharing of analytics methods, discussion of talent upskilling and technology adoption strategies, and collaborative discussion on these potential changes with global Health Authorities.

Interaction of a Cationic Porphyrin and Its Metal Derivatives with G-Quadruplex DNA.

G-quadruplex (GQ) structures formed from guanine-rich sequences are found throughout the genome and are overrepresented in the promoter regions of some oncogenes, at the telomeric ends of eukaryotic chromosomes, and at the 5'-untranslated regions of mRNA. Interaction of small molecule ligands with GQ DNA is an area of great research interest to develop novel anticancer therapeutics and GQ sensors. In this paper we examine the interactions of TMPyP4, its isomer TMPyP2 (containing N-methyl-2-pyridyl substituents, N-Me-2Py) as well as two metal derivatives ZnTMPyP4 and CuTMPyP4 with GQs formed by dT4G4 and dT4G4T in 100 mM K+ or Na+ conditions. The DNA sequences were chosen to elucidate the effect of the 3'-T on the stabilization effect of porphyrins, binding modes, affinities, and stoichiometries determined via circular dichroism melting studies, UV-vis titrations, continuous variation analysis, and fluorescence studies. Our findings demonstrate that the stabilizing abilities of porphyrins are stronger toward (dT4G4)4 as compared to (dT4G4T)4 (ΔTm is 4.4 vs -6.4 for TMPyP4; 12.7 vs 5.7 for TMPyP2; 16.4 vs 12.1 for ZnTMPyP4; and 1.9 vs -8.4 °C for CuTMPyP4) suggesting that the 3'G-tetrad presents at least one of the binding sites. The binding affinity was determined to be moderate (Ka ∼ 106-107 µM-1) with a typical binding stoichiometry of 1:1 or 2:1 porphyrin-to-GQ. In all studies, ZnTMPyP4 emerged as a ligand superior to TMPyP4. Overall, our work contributes to clearer understanding of interactions between porphyrins and GQ DNA.