Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

https://www.njacs.org/wp-content/docs/2010-10-DrugMet-R-Evers.pdf

Membrane transporters in drug development.

Drug-likeness is a key consideration when selecting compounds during the early stages of drug discovery. However, evaluation of drug-likeness in absolute terms does not reflect adequately the whole spectrum of compound quality. More worryingly, widely used rules may inadvertently foster undesirable molecular property inflation as they permit the encroachment of rule-compliant compounds towards their boundaries. We propose a measure of drug-likeness based on the concept of desirability called the quantitative estimate of drug-likeness (QED). The empirical rationale of QED reflects the underlying distribution of molecular properties. QED is intuitive, transparent, straightforward to implement in many practical settings and allows compounds to be ranked by their relative merit. We extended the utility of QED by applying it to the problem of molecular target druggability assessment by prioritizing a large set of published bioactive compounds. The measure may also capture the abstract notion of aesthetics in medicinal chemistry.

/pdf/quantifying-the-chemical-beauty-of-drugs-48hax4bgv8.pdf

Quantifying the chemical beauty of drugs

Most patients who die of cancer have disseminated disease that has become resistant to multiple therapeutic modalities. Ample evidence suggests that the expression of ATP-binding cassette (ABC) transporters, especially the multidrug resistance protein 1 (MDR1, also known as P-glycoprotein or P-gp), which is encoded by ABC subfamily B member 1 (ABCB1), can confer resistance to cytotoxic and targeted chemotherapy. However, the development of MDR1 as a therapeutic target has been unsuccessful. At the time of its discovery, appropriate tools for the characterization and clinical development of MDR1 as a therapeutic target were lacking. Thirty years after the initial cloning and characterization of MDR1 and the implication of two additional ABC transporters, the multidrug resistance-associated protein 1 (MRP1; encoded by ABCC1)), and ABCG2, in multidrug resistance, interest in investigating these transporters as therapeutic targets has waned. However, with the emergence of new data and advanced techniques, we propose to re-evaluate whether these transporters play a clinical role in multidrug resistance. With this Opinion article, we present recent evidence indicating that it is time to revisit the investigation into the role of ABC transporters in efficient drug delivery in various cancer types and at the blood–brain barrier.

/pdf/revisiting-the-role-of-abc-transporters-in-multidrug-42qvst0nsg.pdf

Revisiting the role of ABC transporters in multidrug-resistant cancer

Three ATP-binding cassette (ABC)-superfamily multidrug efflux pumps are known to be responsible for chemoresistance; P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2 (BCRP). These transporters play an important role in normal physiology by protecting tissues from toxic xenobiotics and endogenous metabolites. Hydrophobic amphipathic compounds, including many clinically used drugs, interact with the substrate-binding pocket of these proteins via flexible hydrophobic and H-bonding interactions. These efflux pumps are expressed in many human tumors, where they likely contribute to resistance to chemotherapy treatment. However, the use of efflux-pump modulators in clinical cancer treatment has proved disappointing. Single nucleotide polymorphisms in ABC drug-efflux pumps may play a role in responses to drug therapy and disease susceptibility. The effect of various genotypes and haplotypes on the expression and function of these proteins is not yet clear, and their true impact remains controversial.

ABC multidrug transporters: structure, function and role in chemoresistance

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

/pdf/consensus-guidelines-for-therapeutic-drug-monitoring-in-18b8y5mu39.pdf

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Background: The ability to supplement high-throughput metabolic clearance data with structural information defining the site of metabolism should allow design teams to streamline their synthetic decisions. However, broad application of metabolite identification in early drug discovery has been limited, largely due to the time required for data review and structural assignment. The advent of mass defect filtering and its application toward metabolite scouting paved the way for the development of software automation tools capable of rapidly identifying drug-related material in complex biological matrices. Two semi-automated commercial software applications, MetabolitePilot™ and Mass-MetaSite™, were evaluated to assess the relative speed and accuracy of structural assignments using data generated on a high-resolution MS platform. Results/Conclusion: Review of these applications has demonstrated their utility in providing accurate results in a time-efficient manner, leading to acceleration of metabolite ident...

Software automation tools for increased throughput metabolic soft-spot identification in early drug discovery.

Stability proteomics techniques that do not require drug modifications have emerged as an attractive alternative to affinity purification methods in drug target engagement studies. Two representative techniques include the chemical-denaturation-based SPROX (Stability of Proteins from Rates of Oxidation), which utilizes peptide-level quantification and thermal-denaturation-based TPP (Thermal Proteome Profiling), which utilizes protein-level quantification. Recently, the "OnePot" strategy was adapted for both SPROX and TPP to increase the throughput. When combined with the 2D setup which measures both the denaturation and the drug dose dimensions, the OnePot 2D format offers improved analysis specificity with higher resource efficiency. However, a systematic evaluation of the OnePot 2D format and a comparison between SPROX and TPP are still lacking. Here, we performed SPROX and TPP to identify protein targets of a well-studied pan-kinase inhibitor staurosporine with K562 lysate, in curve-fitting and OnePot 2D formats. We found that the OnePot 2D format provided ∼10× throughput, achieved ∼1.6× protein coverage and involves more straightforward data analysis. We also compared SPROX with the current "gold-standard" stability proteomics technique TPP in the OnePot 2D format. The protein coverage of TPP is ∼1.5 fold of SPROX; however, SPROX offers protein domain-level information, identifies comparable numbers of kinase hits, has higher signal (R value), and requires ∼3× less MS time. Unique SPROX hits encompass higher-molecular-weight proteins, compared to the unique TPP hits, and include atypical kinases. We also discuss hit stratification and prioritization strategies to promote the efficiency of hit followup.

A Comparison of Two Stability Proteomics Methods for Drug Target Identification in OnePot 2D Format.

Synthesis of 12-membered macrocyclic templates and library analogs for PPI

Experimental Screening Strategies to Reduce Attrition Risk

Background: The number of new chemical entities and types of in vitro and in vivo samples that require bioana lysis in drug discovery is large and diverse In addition, method development time is limited as data turnaround is the highest priority These circumstances require that a well-defined set of bioana lysis options be available in short timeframes to triage samples for ana lysis Method: The Apricot Designs Dual Arm (ADDA) instrument is an LC–MS/MS sample delivery system that features a flexible hardware design coupled with software automation to enhance throughput in LC–MS/MS bioana lysis drug discovery The instrument can perform high-throughput LC–MS/ MS (8–10 s/sample) for screening and in vitro bioana lysis, as well as multiplexed LC for traditional gradient or isocratic LC approaches The instrument control software is designed to integrate with DiscoveryQuant™ software (AB Sciex) and a global database of MS/MS conditions Conclusion: Development of the sample delivery platform and its application in high-throughput and gradient LC will be described

Matthew D. Troutman

Papers

Software automation tools for increased throughput metabolic soft-spot identification in early drug discovery.

A Comparison of Two Stability Proteomics Methods for Drug Target Identification in OnePot 2D Format.

Synthesis of 12-membered macrocyclic templates and library analogs for PPI

Experimental Screening Strategies to Reduce Attrition Risk

Resea R ch aR ticle special Focus: Discove R y bioanalysis