Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death

This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a “natural product mimic”, or “NM”, to join the original primary divisions and the designation “natural product botanical”, or “NB”, to cover those botanical “defined mixtures” now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over t...

Natural Products as Sources of New Drugs from 1981 to 2014

This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions and have added a new designation, “natural product botanical” or “NB”, to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74...

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Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010

Natural products: a continuing source of novel drug leads.

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

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The re-emergence of natural products for drug discovery in the genomics era

High-throughput screening (HTS) has been postulated in several quarters to be a contributory factor to the decline in productivity in the pharmaceutical industry. Moreover, it has been blamed for stifling the creativity that drug discovery demands. In this article, we aim to dispel these myths and present the case for the use of HTS as part of a proven scientific tool kit, the wider use of which is essential for the discovery of new chemotypes.

Impact of high-throughput screening in biomedical research

Novel Trends in High-Throughput Screening

Keynote review: in vitro safety pharmacology profiling: an essential tool for successful drug development.

The drastic increase in the costs for discovering and developing a new drug and the high attrition rate of development candidates led to shifting of drug discovery strategy to parallel assessment of comprehensive drug properties along with efficacy. The article reviews the benefits and caveats of implementing comprehensive in vitro tools in early drug discovery and their impact on addressing in vivo ADMET issues. With the proposal of four-barrier profiling paradigm and employment of integrated risk assessment, one can exponentially enhance the predictive power of those in vitro tools by taking into consideration the interplays among those profiling parameters. An 'Exposure Cube' is proposed to promote collective employment of solubility/dissolution, permeability and metabolic clearance to address in vivo exposure and to direct optimization of new chemical entities in drug discovery.

Maximising use of in vitro ADMET tools to predict in vivo bioavailability and safety.

The potential for metabolism-related drug-drug interactions by new chemical entities is assessed by monitoring the impact of these compounds on cytochrome P450 (CYP) activity using well-characterized CYP substrates. The conventional gold standard approach for in vitro evaluation of CYP inhibitory potential uses pooled human liver microsomes (HLM) in conjunction with prototypical drug substrates, often quantified by LC-MS/MS. However, fluorescent CYP inhibition assays, which use recombinantly expressed CYPs and fluorogenic probe substrates, have been employed in early drug discovery to provide low-cost, high-throughput assessment of new chemical entities. Despite its greatly enhanced throughput, this approach has been met with mixed success in predicting the data obtained with the conventional gold standard approach (HLM+LC-MS). The authors find that the predictivity of fluorogenic assays for the major CYP isoforms 3A4 and 2D6 may depend on the quality of the test compounds. Although the structurally more optimized marketed drugs yielded acceptable correlations between the fluorogenic and HLM+LC-MS/MS assays for CYPs 3A4, 2D6, and 2C9 (r 2 = 0.5-0.7; p < 0.005), preoptimization, early discovery compounds yielded poorer correlations (r 2 ≤ 0.2) for 2 of these major isoforms, CYPs 3A4 and 2D6. Potential reasons for the observed differences are discussed. (Journal of Biomolecular Screening 2008;343-353)

https://journals.sagepub.com/doi/pdf/10.1177/1087057108317480

Dejan Bojanic

Papers

Impact of high-throughput screening in biomedical research

Novel Trends in High-Throughput Screening

Keynote review: in vitro safety pharmacology profiling: an essential tool for successful drug development.

Maximising use of in vitro ADMET tools to predict in vivo bioavailability and safety.

Evaluation of Fluorescence- and Mass Spectrometry—Based CYP Inhibition Assays for Use in Drug Discovery: