Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors

Mechanisms underlying the cytotoxicity of a novel quinazolinedione‐based redox modulator, QD 232, in pancreatic cancer cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109817/1/bph12855.pd

Guadecitabine (SGI‐110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135710/1/mol22015991799.pd

From ligand to complexes: inhibition of HIV-1 Integrase by beta-diketo acid metal complexes

Recently, a class of compounds bearing a β-diketo acid moiety have emerged as the most promising lead in anti-HIV-1 IN drug discovery. It is believed that the β-diketo acid pharmacophoric motif could be involved in a functional sequestration of one or both divalent metal ions, which are critical cofactors at the enzyme catalytic site. This would subsequently block the transition state of the IN-DNA complex. In this scenario, it is of paramount importance to acquire information about the mode of action of diketo acids, which could then be useful in the design of new compounds as IN inhibitors

Single amino acid substitution in HIV-1 integrase catalytic core causes a dramatic shift in inhibitor selectivity

HIV-1 integrase (IN) mediates the insertion of viral cDNA into the cell genome, a vital process for replication. This step is catalyzed by two separate DNA reaction events, termed 3’-processing (3’-P) and strand transfer (ST). The second step, ST, is the concerted transesterification reaction that results in the insertion of this DNA product within the host genome. Using this in vitro method we present here the activity of six small molecule IN inhibitors

Design, synthesis, molecular modeling and anti-HIV 1 integrase activity of a series of photoactivable diketo acid-containing inhibitors as affinity probes

Photoaffinity Labelling (PL) is a powerful method in the chemical proteomic approach of protein functions. This method is especially useful for the identification of ligand-binding sites of target proteins and for the investigation of ligand–receptor interactions. The use of affinity-labeled inhibitors to covalently modify the site of interaction and subsequent analysis of the protein have been very effective in providing useful informations about inhibitor binding for a multitude of therapeutic target proteins. Therefore, it could reasonably be applied in drug discovery and development processes. For example, such approach can be used to obtain structural information detailing the association between the enzyme HIV-1 integrase (IN) and inhibitors under development

Preclinical Evaluation of Novel Triphenylphosphonium Salts with Broad-Spectrum Activity

BACKGROUND: Recently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers. METHODOLOGY/PRINCIPAL FINDINGS: A high-throughput MTT-based screen of over 10,000 drug-like small molecules for anti-proliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC₅₀ concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP-treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation. CONCLUSIONS/SIGNIFICANCE: Through our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that show remarkable activity in a panel of cancer cell lines as well as in a mouse model of human breast cancer. The mechanism of action includes mitochondrial localization causing decreased oxygen consumption, increased superoxide production and attenuated growth factor signaling