Cardiac Safety of Kinase Inhibitors – Improving Understanding and Prediction of Liabilities in Drug Discovery Using Human Stem Cell-Derived Models

Ziegler, Ricarda; Häusermann, Fabian; Kirchner, Stephan; Polonchuk, Liudmila

doi:10.3389/fcvm.2021.639824

Cited by 4 publications

(3 citation statements)

References 61 publications

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“…Three out of five drugs with high toxicity, sunitinib, sorafenib, and ponatinib, are shared between FAERS/literature and cellular assays. Additionally, the toxicity of the TKIs on cell viability is similar to that observed in cellular contraction and electrophysiology measurement, which is consistent with a previous study [ 49 ]. Afatinib is ranked as highly cardiotoxic based on mitochondrial and beating assays, with little toxicity found in FAERS or literature; this discrepancy could be due to that the dose of afatinib used in vitro (10 µM) is much higher than its Cmax (0.05 µM) in vivo .…”

Section: Discussionsupporting

confidence: 91%

Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes

Wang

et al. 2023

BMC Med

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Background Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications. Methods Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts. Results Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death. Conclusions Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to eight TKIs, uncovering potential molecular mechanisms in modulating cardiotoxicity. ER stress is activated by multiple TKIs and leads to cardiotoxicity through promoting expression of pro-inflammatory factors and cardiac fetal genes. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity. Graphical Abstract

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Section: Discussionsupporting

confidence: 91%

Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes

Wang

et al. 2023

BMC Med

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“…Overall, our human data are consistent with previous in vivo observations in rats where RKI-1447 attenuated uterine contractility ( 58 ), providing further evidence of therapeutic potential to treat sPTB. To explore potential side effects on affecting smooth muscle cells in other organs, particularly its cardiotoxicity, we performed literature curation and confirmed minimal effects from RKI-1447 ( 59 ). As a potent inhibitor of the Rho kinases ROCKI/II, RKI-1447 has been mainly investigated for therapeutic effects on cancer ( 60 – 62 ), glaucoma ( 63 ), and nonalcoholic fatty liver disease ( 64 ), with less focus on putative effects on modulating uterine contractility.…”

Section: Resultsmentioning

confidence: 99%

Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth

Wang,

Ying

et al. 2024

Sci. Adv.

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Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases.

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“…Ampl is an impedance parameter, which is a key parameter for the estimation of cell viability ( 29 ). In total, four out of eight high TdP risk compounds resulted in decreased cell viability ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Establishment and validation of a torsade de pointes prediction model based on human iPSC‑derived cardiomyocytes

Pan

Wang

2022

Exp Ther Med

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Drug-induced cardiotoxicity is one of the main causes of drug failure, which leads to subsequent withdrawal from pharmaceutical development. Therefore, identifying the potential toxic candidate in the early stages of drug development is important. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a useful tool for assessing candidate compounds for arrhythmias. However, a suitable model using hiPSC-CMs to predict the risk of torsade de pointes (TdP) has not been fully established. The present study aimed to establish a predictive TdP model based on hiPSC-CMs. In the current study, 28 compounds recommended by the Comprehensive in vitro Proarrhythmia Assay (CiPA) were used as training set and models were established in different risk groups, high-and intermediate-risk versus low-risk groups. Subsequently, six endpoints of electrophysiological responses were used as potential model predictors. Accuracy, sensitivity and area under the curve (AUC) were used as evaluation indices of the models and seven compounds with known TdP risk were used to verify model differentiation and calibration. The results showed that among the seven models, the AUC of logistic regression and AdaBoost model was higher and had little difference in both training and test sets, which indicated that the discriminative ability and model stability was good and excellent, respectively. Therefore, these two models were taken as submodels, similar weight was configured and a new TdP risk prediction model was constructed using a soft voting strategy. The classification accuracy, sensitivity and AUC of the new model were 0.93, 0.95 and 0.92 on the training set, respectively and all 1.00 on the test set, which indicated good discrimination ability on both training and test sets. The risk threshold was defined as 0.50 and the consistency between the predicted and observed results were 92.8 and 100% on the training and test sets, respectively. Overall, the present study established a risk prediction model for TdP based on hiPSC-CMs which could be an effective predictive tool for compound-induced arrhythmias.

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Cardiac Safety of Kinase Inhibitors – Improving Understanding and Prediction of Liabilities in Drug Discovery Using Human Stem Cell-Derived Models

Cited by 4 publications

References 61 publications

Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes

Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes

Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth

Establishment and validation of a torsade de pointes prediction model based on human iPSC‑derived cardiomyocytes

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