Current Drug Screening Research Articles

Phenibut: A drug with one too many "buts".

Phenibut is a gamma aminobutyric acid derivative with activity at γ-aminobutyric acid (GABA)B, A and β-phenethylamine receptors. It was developed as a drug in the former Soviet Union to overcome anxiety and improve cognitive function in military personnel. In the last decade, it has made inroads into the European and U.S. markets, being marketed for purported nootropic properties. Here, we summarize the current knowledge on phenibut, its toxicology, pharmacology, adverse health effects, and patterns of use. Publications in peer-reviewed journals were searched in PubMed, Web of Science, and Google Scholar databases. Available literature points to adverse side effects associated with intoxication, withdrawal, and addiction to phenibut. Some of these effects can be life-threatening, requiring hospitalization and therapeutic interventions. Supportive efforts are often complicated by a lack of knowledge regarding phenibut's toxicology and pharmacology. Ingestion of phenibut was often associated with concomitant use of other substances of abuse. As control over its online marketing seems unrealistic, current efforts need to be focused on the addition of phenibut to current drug screening tests and the development of generally accepted treatment strategies for phenibut-associated toxicities.

Chemoselective Silver-Catalyzed Nitrene Transfer: Tunable Syntheses of Azepines and Cyclic Carbamimidates.

Azepines and their saturated azepane counterparts are important moieties in bioactive molecules but are under-represented in current drug screening libraries. Herein, we report a mild and efficient azepine formation via silver-catalyzed dearomative nitrene transfer. A 2,2,2-trichloroethoxysulfonyl (Tces)-protected carbamimidate nitrene precursor, coupled with the appropriate ligand for silver, is essential for achieving the unexpected chemoselectivity between arene dearomatization and benzylic C(sp3)-H amination. Potential applications in the late-stage diversification of azepines to complex molecular scaffolds and diastereoselective hydrogenations to sp3-rich derivatives are also highlighted.

MODL-09. IMAGE-BASED SCREENING IN MEDULLOBLASTOMA REVEALS TUMOR-SUPPRESSIVE EFFECTS OF THE NEUROPROTECTIVE AGENT URMC-12K

Abstract BACKGROUND Enhanced motility and the invasive behavior of medulloblastoma (MB) influence microenvironment interactions and may promote distant spread. Current drug screening focuses on cytotoxic agents, leaving subtle but potentially therapeutically relevant drug phenotypes associated with motility and invasiveness unrecognized. The serine/threonine kinase MAP4K4 is upregulated in MB and promotes invasiveness1,2. Toxicities associated with existing MAP4K4 inhibitors in the CNS prevented further pre-clinical evaluation. URMC-12k is a novel MAP4K inhibitor identified as a motor-neuron-protective agent in ALS. Using advanced imaging approaches, we investigated URMC-12k as a tumor-suppressive drug in MB and characterized its effects at the molecular, cellular, and tissue levels. METHODS We use cell-based 3D invasion assays and quantitative microscopy to assess tumor-restraining activities of URMC-12k, and machine learning to detect URMC-12k phenotypes associated with repressed motility. We use tissue and zebrafish larval models to explore URMC-12k effects on cell and tissue viability and anti-invasion efficacy. We determined URMC-12k targets in MB cells using phosphoproteomics. RESULTS URMC-12k outcompetes existing MAP4K4 inhibitors in repressing basal and growth-factor-induced matrix invasion with no detectable effects on vertebrate developmental processes. A computational model trained to detect morphological alterations in the actin cytoskeleton associated with cell dynamics established a firm correlation between the URMC-12k-repressed motile behavior and alterations in the tumor cell actin cytoskeleton. Quantitative imaging further revealed that URMC-12k promoted increased cell clustering and reduced deposition of extracellular vesicles. Phosphoproteomics identified proteins involved in cell adhesion organization and vesicle trafficking as potential molecular effectors targeted by URMC-12k. CONCLUSIONS URMC-12k effectively inhibits MB cell migration and displays no toxicities at effective concentrations. The regulation of cell-cell adhesion molecules and the deposition of extracellular vesicles revealed by URMC-12k are tumor-promoting, druggable mechanisms of MAP4Ks in MB. 1. 1Migliavacca, J., et al. Commun Biol5, (2022). 2. 2Tripolitsioti, D. et al. Oncotarget9, 23220–23236 (2018).

An economical, high-throughput protein-protein interaction modulator drug screening technique based on surface-enhanced Raman scattering

Increasing identification of protein-protein interaction (PPI) targets creates opportunities for drug discovery. However, the current drug screening strategies are costly and reagent-consuming, which hinders the progress in PPI modulator drug discovery. The primary obstacle lies in the inability to achieve molecular fishing with existing technology. Herein, we present a novel high-throughput, homogeneous-phase screening assay for PPI modulator discovery called “SERScreen”, based on a magnetic field-amplified surface-enhanced Raman spectroscopy (SERS). Two high-affinity proteins are fixed respectively on the magnetic beads (MBs) and the SERS tags, and the cross-linking of two nanoprobes induced by PPI enables strong SERS signals. Candidate modulators interfere with the PPI according to higher affinity toward one protein, resulting in a significant reduction in SERS intensity above the MBs. We established a potential drug screening platform for PD-1/PD-L1, and demonstrated its feasiblility not only with known inhibitors (Durvalumab and BMS-202), but also with a small-molecule combinatorial library, successfully identifying two new candidate inhibitors via the molecular fishing of SERScreen. Furthermore, the anticancer mechanism of two candidates was discussed. As an ultrasensitive, low reagent consumption (2 µL sample solution), high-throughput screening technique in the PPI modulator discovery, SERScreen offers an effective solution for molecular fishing from complex samples and displays high compatibility with automatic measurement equipment.

Streptomyces-based whole-cell biosensors for detecting diverse cell envelope-targeting antibiotics

Cell envelope-targeting antibiotics are potent therapeutic agents against various bacterial infections. The emergence of multiple antibiotic-resistant strains underscores the significance of identifying potent antimicrobials specifically targeting the cell envelope. However, current drug screening approaches are tedious and lack sufficient specificity and sensitivity, warranting the development of more efficient methods. Genetic circuit-based whole-cell biosensors hold great promise for targeted drug discovery from natural products. Here, we performed comparative transcriptomic analysis of Streptomyces coelicolor M1146 exposed to diverse cell envelope-targeting antibiotics, aiming to identify regulatory elements involved in perceiving and responding to these compounds. Differential gene expression analysis revealed significant activation of VanS/R two-component system in response to the glycopeptide class of cell envelope-acting antibiotics. Therefore, we engineered a pair of VanS/R-based biosensors that exhibit functional complementarity and possess exceptional sensitivity and specificity for glycopeptides detection. Additionally, through promoter screening and characterization, we expanded the biosensor's detection range to include various cell envelope-acting antibiotics beyond glycopeptides. Our genetically engineered biosensor exhibits superior performance, including a dynamic range of up to 887-fold for detecting subtle antibiotic concentration changes in a rapid 2-h response time, enabling high-throughput screening of natural product libraries for antimicrobial agents targeting the bacterial cell envelope.

High-Throughput Small Molecule Drug Screening For Age-Related Sleep Disorders Using Drosophila melanogaster.

Sleep, an essential component of health and overall well-being, often presents challenges for older individuals who frequently experience sleep disorders characterized by shortened sleep duration and fragmented patterns. These sleep disruptions also correlate with an increased risk of various illnesses in the elderly, including diabetes, cardiovascular diseases, and psychological disorders. Unfortunately, existing drugs for sleep disorders are associated with significant side effects such as cognitive impairment and addiction. Consequently, the development of new, safer, and more effective sleep disorder medications is urgently needed. However, the high cost and lengthy experimental duration of current drug screening methods remain limiting factors. This protocol describes a cost-effective and high-throughput screening method that utilizes Drosophila melanogaster, a species with a highly conserved sleep regulation mechanism compared to mammals, making it an ideal model for studying sleep disorders in the elderly. By administering various small compounds to aged flies, we can assess their effects on sleep disorders. The sleep behaviors of these flies are recorded using an infrared monitoring device and analyzed with the open-source data package Sleep and Circadian Analysis MATLAB Program 2020 (SCAMP2020). This protocol offers a low-cost, reproducible, and efficient screening approach for sleep regulation. Fruit flies, due to their short life cycle, low husbandry cost, and ease of handling, serve as excellent subjects for this method. As an illustration, Reserpine, one of the tested drugs, demonstrated the ability to promote sleep duration in elderly flies, highlighting the effectiveness of this protocol.

Tissue-engineered heart chambers as a platform technology for drug discovery and disease modeling.

Current drug screening approaches are incapable of fully detecting and characterizing drug effectiveness and toxicity of human cardiomyocytes. The pharmaceutical industry uses mathematical models, cell lines, and in vivo models. Many promising drugs are abandoned early in development, and some cardiotoxic drugs reach humans leading to drug recalls. Therefore, there is an unmet need to have more reliable and predictive tools for drug discovery and screening applications. Biofabrication of functional cardiac tissues holds great promise for developing a faithful 3D in vitro disease model, optimizing drug screening efficiencies enabling precision medicine. Different fabrication techniques including molding, pull spinning and 3D bioprinting were used to develop tissue-engineered heart chambers. The big challenge is to effectively organize cells into tissue with structural and physiological features resembling native tissues. Some advancements have been made in engineering miniaturized heart chambers that resemble a living pump for drug screening and disease modeling applications. Here, we review the currently developed tissue-engineered heart chambers and discuss challenges and prospects.

DIPG-39. New preclinical models for Diffuse Midline Glioma

Malignant brain tumors are the leading cause of childhood death in Germany, with Diffuse Midline Glioma (DMG) being the most lethal of all paediatric brain tumors. Current treatment strategies are limited to irradiation which prolongs survival only by a few months. Preclinical studies have identified effective drug candidates, but translation into the clinic remains a major obstacle. It is known that interactions between tumor cells and components of the TME (tumor microenvironment), such as cell to cell contacts between malignant and non-malignant cells or secreted factors, can increase therapy resistance and progression of brain tumors. However, these important factors are not present in most conventional cell culture models for drug testing. Consequently, there is a need for more realistic DMG models to improve the relevance and translational potential of current drug screening. Therefore, the goal of this study was to develop a new DMG model for drug testing, consisting of induced pluripotent stem cell (iPSC) derived human brain cells and patient derived DMG cells to better mimic the complex tumor microenvironment. We co-cultured three-dimensional cerebral organoids with DMG tumor spheres resulting in the formation of DMG-Brain-Organoids (DBO). Preliminary results show that co-culture induces distinct tumor cell subpopulations corresponding to those detected in DMG tumors by single cell RNA sequencing (Filbin et al., 2018). These subpopulations mainly differ in their proliferative capacity and their differential response to clinical interventions may be critical for therapeutic success. DBOs subjected to drug treatments (single or combination) were sectioned and individual therapy effects on tumor cell subpopulations and proliferative capacity were monitored using multiplexed immunofluorescence imaging. By observing drug effects in a realistic setup, we hope to improve the predictive power of our preclinical drug screens and to find new combination therapies for DMG.

High-throughput drug screening models of mature adipose tissues which replicate the physiology of patients’ Body Mass Index (BMI)

Obesity is a complex and incompletely understood disease, but current drug screening strategies mostly rely on immature in vitro adipose models which cannot recapitulate it properly. To address this issue, we developed a statistically validated high-throughput screening model by seeding human mature adipocytes from patients, encapsulated in physiological collagen microfibers. These drop tissues ensured the maintenance of adipocyte viability and functionality for controlling glucose and fatty acids uptake, as well as glycerol release. As such, patients’ BMI and insulin sensitivity displayed a strong inverse correlation: the healthy adipocytes were associated with the highest insulin-induced glucose uptake, while insulin resistance was confirmed in the underweight and severely obese adipocytes. Insulin sensitivity recovery was possible with two type 2 diabetes treatments, rosiglitazone and melatonin. Finally, the addition of blood vasculature to the model seemed to more accurately recapitulate the in vivo physiology, with particular respect to leptin secretion metabolism.

Photolithographic Fabrication of Semi 3-D Microstructures Composed of Flexible Hydrogel Sheet for in Vivo-like Cell Culture System

Insufficient reliability of current drug screening by cell-based assay has been one of the factors in the poor success rate in drug development. To improve the situation, we proposed a cell culture system using semi 3-D hydrogel microstructures as cell culture scaffolds. Because of its flexibility and permeability, the microstructure was expected to enhance the physiological function of cells. We developed a simple method of fabricating the unique hydrogel microstructures composed of hydroxypropyl cellulose through photolithography. Functionalization with poly(styrene-co-maleic anhydride) gained their cell adhesion, and it was demonstrated that several kinds of cells were incubated on the cell culture scaffolds.

Fluid Shear Stress Induces Drug Resistance to Doxorubicin and Paclitaxel in the Breast Cancer Cell Line MCF7

AbstractCirculating tumor cells (CTCs) are known to have cancer stem cell (CSC) properties and survive physiological conditions of fluid shear stress (FSS). However, current chemotherapy screening techniques do not adequately recapitulate this FSS environment and are not predictive of a drug response. In this study, MCF7 and MDA‐MB‐231 cells under FSS are used as an in vitro model of CTCs. The effects of doxorubicin (DOX) and paclitaxel on sheared cells using WST8 assay and stemness (CD44+/CD24−) and apoptosis (Annexin V+/7‐AAD+) using flow cytometry are tested. Quantitative polymerase chain reaction is used to test gene expression. It is shown that suspension‐cultured and FSS treated MCF7 cells increase in drug resistance, especially with DOX. There is a synergistic increase in the CD44+/CD24− CSC‐like population and an increase in drug resistance‐related gene expression in MCF7 cells co‐treated with FSS and drugs. There is also a correlated increase in STAT3 and NANOG expression under FSS. To the best of the authors' knowledge, this is the first report to suggest that the increase in CSC‐like cells from FSS contributes to drug resistance via the STAT3/NANOG pathway. This increase in CTC drug resistance also highlights the importance of implementing FSS, which is unavailable in current drug screening techniques.

Impedance-based detection of Schistosoma mansoni larvae viability for drug screening.

Human schistosomiasis is a neglected tropical disease caused by trematodes, affecting almost 250 million people worldwide. For the past 30 years, treatment has relied on the large-scale administration of praziquantel. However, concerns regarding the appearance of drug-resistance parasites require efforts in identifying novel classes of suitable drugs against schistosomiasis. The current drug screening system is manual, slow and subjective. We present here a microfluidic platform capable of detecting changes in viability of Schistosoma mansoni larvae (Newly Transformed Schistosomula, NTS). This platform could serve as a pre-screening tool for the identification of drug candidates. It is composed of a pair of coplanar electrodes integrated in a microfluidic channel for the detection and quantification of NTS motility. Comparison of viability detection by using our platform with the standard visual evaluation shows that our method is able to reliably detect viable and non-viable NTS at high sensitivity, also in case of low-motility parasites, while enabling a 10 fold decrease in sample consumption.

Biomimetic 3D Tissue Models for Advanced High-Throughput Drug Screening.

Most current drug screening assays used to identify new drug candidates are 2D cell-based systems, even though such in vitro assays do not adequately re-create the in vivo complexity of 3D tissues. Inadequate representation of the human tissue environment during a preclinical test can result in inaccurate predictions of compound effects on overall tissue functionality. Screening for compound efficacy by focusing on a single pathway or protein target, coupled with difficulties in maintaining long-term 2D monolayers, can serve to exacerbate these issues when using such simplistic model systems for physiological drug screening applications. Numerous studies have shown that cell responses to drugs in 3D culture are improved from those in 2D, with respect to modeling in vivo tissue functionality, which highlights the advantages of using 3D-based models for preclinical drug screens. In this review, we discuss the development of microengineered 3D tissue models that accurately mimic the physiological properties of native tissue samples and highlight the advantages of using such 3D microtissue models over conventional cell-based assays for future drug screening applications. We also discuss biomimetic 3D environments, based on engineered tissues as potential preclinical models for the development of more predictive drug screening assays for specific disease models.

A critical analysis of national policy relating to legal highs.

New psychoactive substances or 'legal highs' are widely used by young people. Government attempts to ban the substances have been unsuccessful as they are quickly replaced by new compounds. The substances cannot be detected by current drug screening. This article explores UK policy on legal highs, to draw international comparisons, to establish recommendations for tackling the problem, and to highlight potential implications for UK policy. Policymakers should consider means of regulation including of the sale of legal highs and restrictions on supply. They should examine use of holding measures while harm is evaluated, consider classifying substances based on their potential for harm, and create education programmes on the legal implications of buying legal highs as well as harm caused.

Drug repurposing screen identifies lestaurtinib amplifies the ability of the poly (ADP-ribose) polymerase 1 inhibitor AG14361 to kill breast cancer associated gene-1 mutant and wild type breast cancer cells.

IntroductionBreast cancer is a devastating disease that results in approximately 40,000 deaths each year in the USA. Current drug screening and chemopreventatitive methods are suboptimal, due in part to the poor specificity of compounds for cancer cells. Poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARPi)-mediated therapy is a promising approach for familial breast cancers caused by mutations of breast cancer-associated gene-1 and -2 (BRCA1/2), yet drug resistance frequently occurs during the treatment. Moreover, PARPis exhibit very little effect on cancers that are proficient for DNA repair and clinical efficacy for PARPis as single-agent therapies has yet to be illustrated.MethodsUsing a quantitative high-throughput screening approach, we screened a library containing 2,816 drugs, most of which are approved for human or animal use by the Food and Drug Administration (FDA) or other countries, to identify compounds that sensitize breast cancer cells to PARPi. After initial screening, we performed further cellular and molecular analysis on lestaurtinib, which is an orally bioavailable multikinase inhibitor and has been used in clinical trials for myeloproliferative disorders and acute myelogenous leukemia.ResultsOur study indicated that lestaurtinib is highly potent against breast cancers as a mono-treatment agent. It also strongly enhanced the activity of the potent PARPi AG14361 on breast cancer cell growth both in vitro and in vivo conditions. The inhibition of cancer growth is measured by increased apoptosis and reduced cell proliferation. Consistent with this, the treatment results in activation of caspase 3/7, and accumulation of cells in the G2 phase of the cell cycle, irrespective of their BRCA1 status. Finally, we demonstrated that AG14361 inhibits NF-κB signaling, which is further enhanced by lestaurtinib treatment.ConclusionsLestaurtinib amplifies the ability of the PARP1 inhibitor AG14361 to kill BRCA1 mutant and wild-type breast cancer cells, at least in part, by inhibiting NF-κB signaling. Each of these drugs has been approved for clinical trials for several different cancers, thus, their combination treatment should be applicable for a breast cancer trial in the future.

Combine use of Intracellular Calcium and Sarcolemma Voltage Measurements to Distinguish Mixed Channel Effects in Human Induced Plutipotent Stem Cells Derived Cardiomyocytes (HIPSC-CMS)

Blockade of the human ether-a-go-go-related gene (hERG) ion channel is a marker for pro-arrhythmic risk. However, the extent of hERG channel inhibition is poorly correlated with action potential duration (APD) prolongation in vitro, due to multi-channel block. Subsequently, compounds which block multiple ion channels may be overlooked by pre-clinical safety screening when measuring voltage alone, with the potential risk of late stage drug attrition and withdrawal. In this work we propose optical measurements of voltage and intracellular calcium ([Ca2+]i) in hiPSC-CMs as an alternative to the current drug screening methods to distinguish mixed action drugs in early stages. We used hiPSC-CMs loaded with 3μM di-4-ANEPPS to record membrane potential and 1μM Fura 4-AM to measure [Ca2+]i from areas of iPSCs using CellOPTIQ platform (Clyde Biosciences, Glasgow UK). Fluorescence signals were digitized at 10kHz and analyzed off-line using proprietary software. Mixed ion channel blockade was mimicked by the co-administration of E-4031 (hERG blocker) and Nifedipine (Ca2+ channel blocker). The results showed that at a critical combined concentrations (e.g. 30nM E4031 + 30nM Nifedipine) which individually prolonged and shortened APD at 75% of repolarisation (APD75) respectively, in combination did not significantly change APD75 from baseline (APD75 6.5 ± 7% of control), whereas [Ca2+]i was markedly reduced (by 18 ± 1.2% change, p<0.05). Low concentrations of Verapamil (30nM), an antiarrhythmic drug with known mixed hERG and L-type Ca2+ channel activity, had no significant effect on APD (APD75 1.5 ± 0.7%) whereas the amplitude of Ca2+ transient was significantly reduced (by 45 ± 8%, p<0.05). In conclusion, simultaneous measurements of [Ca2+]i and voltage provides a convenient indicator of mixed ion channel effects when screening for drug-induced cardiotoxicity.

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

The current drug screening models are deficient, particularly in detecting cardiac side effects. Human stem cell-derived cardiomyocytes could aid both early cardiotoxicity detection and novel drug discovery. Work over the last decade has generated human embryonic stem cells as potentially accurate sources of human cardiomyocytes, but ethical constraints and poor efficacy in establishing cell lines limit their use. Induced pluripotent stem cells do not require the use of human embryos and have the added advantage of producing patient-specific cardiomyocytes, allowing both generic and disease- and patient-specific pharmacological screening, as well as drug development through disease modelling. A critical question is whether sufficient standards have been achieved in the reliable and reproducible generation of 'adult-like' cardiomyocytes from human fibroblast tissue to progress from validation to safe use in practice and drug discovery. This review will highlight the need for a new experimental system, assess the validity of human induced pluripotent stem cell-derived cardiomyocytes and explore what the future may hold for their use in pharmacology.

Microfluidic technique to measure intratumoral transport and calculate drug efficacy shows that binding is essential for doxorubicin and release hampers Doxil

Intratumoral transport and binding are important mechanisms that determine the efficacy of cancer drugs. Current drug screening methods rely heavily on monolayers of cancer cells, which overlook the contribution of tissue-level transport and binding. To quantify these factors, we developed a method that couples an in vitro, drug-delivery device containing a three-dimensional cell mass and a mathematical model of drug diffusion, binding to DNA, release from carriers, and clearance. Spheroids derived from LS174T human colon carcinoma cells were inserted into rectangular chambers to form rectangular cell masses (tissue) and subjected to continuous medium perfusion. To simulate drug delivery and clearance, the tissues were treated with doxorubicin followed by drug-free medium. To evaluate the effect of liposome encapsulation, tissues were treated with liposome-encapsulated doxorubicin (Doxil). Spatiotemporal dynamics of drug distribution and apoptosis was measured by fluorescence microscopy. The diffusivity and DNA binding constant of doxorubicin were determined by fitting experimental data to the mathematical model. Results show that an ideal combination of diffusivity, binding constant, clearance rate, and cytotoxicity contribute to the high therapeutic efficacy of doxorubicin. There was no detectable release of doxorubicin from Doxil in the tissues. The rate of doxorubicin release, evaluated by fitting experimental data to the mathematical model, was below therapeutically effective levels. These results show that despite enhanced systemic circulation obtained by liposome encapsulation, the therapeutic effect of Doxil is limited by slow intratumoral drug release. The experimental and computational methods developed here to calculate drug efficacy provide mechanisms to explain poor performance of drug candidates, and enable design of more successful cancer drugs.

An AFM-FET Biosensor for Proteomic Screening

 Abstract—An atomic force microscope (AFM) and a field effect transistor (FET) were integrated into one functioning novel biosensor to probe single molecular interactions between biomolecules, such as proteins and ligands. The interactions between avidin-biotin complexes were studied using the AFM-FET biosensor. Biotin molecules were attached to the AFM cantilever via flexible polyethylene glycol cross-linkers, and avidin molecules were bound to the palladium gate surface of the FET via the cross-linker molecules, cystamine and glutaraldehyde. The force of the AFM and the FET current between the drain and source was measured as a function of distance when the biotin molecules approached and retracted from the avidin molecules. The measurement data showed that the FET current changed abruptly when binding and unbinding events occurred between the two molecules. This change in the current was generated from the corresponding electric potential, which was related to the magnitude of unbinding force during the binding and unbinding events. The relationship suggests that the AFM-FET biosensor can provide potential voltages generated during the biding and unbinding events. This additional information on molecular interactions at the single molecular level could potentially be used as a quantitative and efficient method for detecting single molecular interactions. The novel AFM-FET biosensor is potentially advantageous over current drug screening methods based on microfluidics, due to the AFM-FET ability to record single interactions more quickly and accurately.

Stem Cells for Drug Screening

Current drug screening methods are insufficiently predictive of clinical toxicity and efficacy. Recent advances in stem cell technology have the potential to improve drug screening. For tests of cardiotoxicity and efficacy of cardioactive drugs, cardiomyocytes derived from human embryonic stem cells and/or human induced pluripotent stem cells, collectively termed human pluripotent stem cells (hPSCs), have been utilized as model alternatives to current drug screening platforms. In this review, we report on recent advances in the differentiation of hPSCs to cardiomyocytes and summarize the evidence for pharmacological responses in hPSC-derived cardiomyocytes.