Small Molecule Protein Kinase Inhibitors Research Articles

Potential protein kinase inhibitors that target G-quadruplex DNA structures in the human telomeric regions.

Telomeric regions contain Guanine-rich sequences arranged in a planar manner and connected by Hoogsteen hydrogen bonds that can fold into G-quadruplex (G4) DNA structures, and can be stabilized by monovalent metal cations. The presence of G4 DNA holds significance in cancer-related processes, especially due to their regulatory potential at transcriptional and translational levels of oncogene and tumor suppressor genes. The objective of this current research is to explore the evolving realm of FDA-approved protein kinase inhibitors, with a specific emphasis on their capacity to stabilize the G4 DNA structures formed at the human telomeric regions. This involves investigating the possibility of repurposing FDA-approved protein kinase inhibitors as a novel approach for targeting multiple cancer types. In this context, we have selected 16 telomeric G4 DNA structures as targets and 71 FDA-approved small-molecule protein kinase inhibitors as ligands. To investigate their binding affinities, molecular docking of human telomeric G4 DNA with nuclear protein kinase inhibitors and their corresponding co-crystalized ligands were performed. We found that Ponatinib and Lapatinib interact with all the selected G4 targets, the binding free energy calculations, and molecular dynamic simulations confirm their binding efficacy and stability. Thus, it is hypothesized that Ponatinib and Lapatinib may stabilize human telomeric G4 DNA in addition to their ability to inhibit BCR-ABL and the other members of the EGFR family. As a result, we also hypothesize that the stabilization of G4 DNA might represent an additional underlying mechanism contributing to their efficacy in exerting anti-cancer effects.

An Update on Protein Kinases as Therapeutic Targets-Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases.

Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor-kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II).

An Update on Protein Kinases as Therapeutic Targets-Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein-Protein Interactions.

Human protein kinases are highly-sought-after drug targets, historically harnessed for treating cancer, cardiovascular disease, and an increasing number of autoimmune and inflammatory conditions. Most current treatments involve small molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP-binding pocket. As a result, these compounds are often poorly selective and highly toxic. Part I of this series reviews the role of PKC isoforms in various human diseases, featuring cancer and cardiovascular disease, as well as translational examples of PKC modulation applied to human health and disease. In the present Part II, we discuss alternative allosteric binding mechanisms for targeting PKC, as well as novel drug platforms, such as modified peptides. A major goal is to design protein kinase modulators with enhanced selectivity and improved pharmacological properties. To this end, we use molecular docking analysis to predict the mechanisms of action for inhibitor-kinase interactions that can facilitate the development of next-generation PKC modulators.

Evaluation of the FDA-approved kinase inhibitors to uncover the potential repurposing candidates targeting ABC transporters in multidrug-resistant cancer cells: an in silico approach

Multiple drug resistance (MDR) is characterized by the resistance of cancer cells to a broad spectrum of anticancer drugs. The main mechanism underlying the MDR phenotype is the overexpression of ATP-binding cassette (ABC) transporters by promoting active drug efflux from cancer cells. Some small-molecule protein kinase inhibitors have been found to overcome MDR by inhibiting ABC transporters as substrates or modulators. This study investigated the chemical activity of 58 FDA-approved anticancer kinase inhibitors against three multidrug resistance-related proteins. The studied proteins are ATP-Binding Cassette Sub-Family B Member 1 (ABCB1), ATP-Binding Cassette Subfamily C Member 1 (ABCC1), and ATP-binding cassette superfamily G member 2 (ABCG2). The drug-binding domain and ATP binding sites of the proteins were considered the kinase inhibitors’ probable target. High-throughput virtual screening and molecular docking were employed to find the hit drugs, and the drugs with the highest binding affinity were further evaluated using the molecular dynamics (MD) simulation. The virtual screening revealed that several kinase inhibitors could be considered potential inhibitors of ABCB1, ABCC1, and ABCG2, among which larotrectinib, entrectinib, and infigratinib showed the highest binding affinity, respectively. Based on the obtained results from MD simulation, these drugs can form strong interactions with the essential residues of the target proteins. In silico investigation revealed that larotrectinib, entrectinib, and infigratinib can target the key residues of the studied proteins. Therefore, these approved kinase inhibitors could be considered potential therapies for MDR cancers by targeting these transporters. Communicated by Ramaswamy H. Sarma

The small-molecule kinase inhibitor ceritinib, unlike imatinib, causes a significant disturbance of lipid membrane integrity: A combined experimental and MD study

Ceritinib and imatinib are small-molecule protein kinase inhibitors which are applied as therapeutic agents against various diseases. The fundamentals of their clinical use, i.e. their pharmacokinetics as well as the mechanisms of the inhibition of the respective kinases, are relatively well studied. However, the interaction of the drugs with membranes, which can be a possible cause of side effects, has hardly been investigated so far. Therefore, we have characterized the interaction of both drugs with lipid membranes consisting of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) in the absence and in the presence of cholesterol. For determining the membrane impact of both drugs on a molecular level, different experimental (NMR, ESR, fluorescence) and theoretical (MD simulations) approaches were applied. The data show that ceritinib, in contrast to imatinib, interacts more effectively with membranes significantly affecting various physico-chemical membrane parameters like membrane order and transmembrane permeation of polar solutes. The pronounced membrane impact of ceritinib can be explained by a strong affinity of the drug towards POPC which competes with the POPC-cholesterol interaction by that attenuating the ordering effect of cholesterol. The data are relevant for understanding putative toxic and cytotoxic side effects of these drugs such as the triggering of cell lysis or apoptosis.

The Absolute Bioavailability and Absorption, Metabolism, and Excretion of Ipatasertib, a Potent and Highly Selective Protein Kinase B (Akt) Inhibitor.

Ipatasertib (GDC-0068) is a potent, highly selective, small-molecule inhibitor of protein kinase B (Akt) being developed by Genentech/Roche as a single agent and in combination with other therapies for the treatment of cancers. To fully understand the absorption, metabolism, and excretion of ipatasertib in humans, an open-label study using 14C-radiolabeled ipatasertib was completed to characterize the absolute bioavailability (period 1) and mass balance and metabolite profiling (period 2). In period 1, subjects were administered a 200 mg oral dose of ipatasertib followed by an 80 μg (800 nCi) intravenous dose of [14C]-ipatasertib. In period 2, subjects received a single oral dose containing approximately 200 mg (100 μCi) [14C]-ipatasertib. In an integrated analytical strategy, accelerator mass spectrometry was applied to measure the 14C microtracer intravenous pharmacokinetics in period 1 and fully profile plasma radioactivity in period 2. The systemic plasma clearance and steady-state volume of distribution were 98.8 L/h and 2530 L, respectively. The terminal half-lives after oral and intravenous administrations were similar (26.7 and 27.4 hours, respectively) and absolute bioavailability of ipatasertib was 34.0%. After a single oral dose of [14C]-ipatasertib, 88.3% of the administered radioactivity was recovered with approximately 69.0% and 19.3% in feces and urine, respectively. Radioactivity in feces and urine was predominantly metabolites with 24.4% and 8.26% of dose as unchanged parent, respectively; indicating that ipatasertib had been extensively absorbed and hepatic metabolism was the major route of clearance. The major metabolic pathway was N-dealkylation mediated by CYP3A, and minor pathways were oxidative by cytochromes P450 and aldehyde oxidase. SIGNIFICANCE STATEMENT: The study provided definitive information regarding the absolute bioavailability and the absorption, metabolism, and excretion pathways of ipatasertib, a potent, novel, and highly selective small-molecule inhibitor of protein kinase B (Akt). An ultrasensitive radioactive counting method, accelerator mass spectrometry was successfully applied for 14C-microtracer absolute bioavailability determination and plasma metabolite profiling.

Nerve trunk healing and neuroma formation after nerve transection injury.

The nerve trunk healing process of a transected peripheral nerve trunk is composed of angiogenesis, nerve fiber regeneration, and scarring. Nerve trunk healing and neuroma formation probably share identical molecular mediators and similar regulations. At the nerve transection site, angiogenesis is sufficient and necessary for nerve fiber regeneration. Angiogenesis and nerve fiber regeneration reveal a positive correlation in the early time. Scarring and nerve fiber regeneration show a negative correlation in the late phase. We hypothesize that anti-angiogenesis suppresses neuromas. Subsequently, we provide potential protocols to test our hypothesis. Finally, we recommend employing anti-angiogenic small-molecule protein kinase inhibitors to investigate nerve transection injuries.

Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer

Small molecule protein kinase inhibitors (PKIs) have become an effective strategy for cancer patients. However, hepatotoxicity is a major safety concern of these drugs, since the majority are reported to increase transaminases, and few of them (Idelalisib, Lapatinib, Pazopanib, Pexidartinib, Ponatinib, Regorafenib, Sunitinib) have a boxed label warning. The exact rate of PKI-induced hepatoxicity is not well defined due to the fact that the majority of data arise from pre-registration or registration trials on fairly selected patients, and the post-marketing data are often based only on the most severe described cases, whereas most real practice studies do not include drug-related hepatotoxicity as an end point. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing PKIs should be carefully pre-evaluated and monitored. The management of this complication requires an individually tailored reappraisal of the risk/benefit ratio, especially in patients who are responding to therapy. This review reports the currently available data on the risk and management of hepatotoxicity of all the approved PKIs.

Overcoming translational barriers in H3K27-altered diffuse midline glioma: Increasing the drug-tumor residence time.

H3K27-altered diffuse midline glioma (DMG) is the deadliest pediatric brain tumor; despite intensive research efforts, every clinical trial to date has failed. Is this because we are choosing the wrong drugs? Or are drug delivery and other pharmacokinetic variables at play? We hypothesize that the answer is likely a combination, where optimization may result in a much needed novel therapeutic approach. We used in vitro drug screening, patient samples, and shRNA knockdown models to identify an upregulated target in DMG. A single small molecule protein kinase inhibitor with translational potential was selected for systemic and direct, loco-regional delivery to patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM). Pharmacokinetic studies were conducted in non-tumor bearing rats. Aurora kinase (AK) inhibitors demonstrated strong antitumor effects in DMG drug screens. Additional in vitro studies corroborated the importance of AK to DMG survival. Systemic delivery of alisertib showed promise in subcutaneous PDX but not intracranial GEMM and PDX models. Repeated loco-regional drug administration into the tumor through convection-enhanced delivery (CED) was equally inefficacious, and pharmacokinetic studies revealed rapid clearance of alisertib from the brain. In an effort to increase the drug to tumor residence time, continuous CED over 7 days improved drug retention in the rodent brainstem and significantly extended survival in both orthotopic PDXs and GEMMs. These studies provide evidence for increasing drug-tumor residence time of promising targeted therapies via extended CED as a valuable treatment strategy for DMG.

Novel Effective Small-Molecule Inhibitors of Protein Kinases Related to Tau Pathology in Alzheimer's Disease

Background: Alzheimer's disease (AD) drugs in therapy are limited to acetylcholine esterase inhibitors and memantine. Newly developed drugs against a single target structure have an insufficient effect onsymptomaticAD patients. Results: Novel aromaticallyanellated pyridofuranes have been evaluated for inhibition of AD-relevant protein kinases cdk1, cdk2, gsk-3b and Fyn. Best activities have been found for naphthopyridofuranes with a hydroxyl function as part of the 5-substituent and a hydrogen or halogen substituent in the 8-position. Best results in nanomolar ranges were found for benzopyridofuranes with a 6-hydroxy and a 3-alkoxy substitution or an exclusive 6-alkoxy substituent. Conclusion: First lead compounds were identified inhibiting two to three kinases in nanomolar ranges to be qualified as aninnovative approach forAD multitargeting.

Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC Library.

Small-molecule protein kinase inhibitors are used for the treatment of cancer, but off-target effects hinder their clinical use. Especially off-target activation of the pregnane X receptor (PXR) has to be considered, as it not only governs drug metabolism and elimination, but also can promote tumor growth and cancer drug resistance. Consequently, PXR antagonism has been proposed for improving cancer drug therapy. Here we aimed to identify small-molecule kinase inhibitors of the Tübingen Kinase Inhibitor Collection (TüKIC) compound library that would act also as PXR antagonists. By a combination of in silico screen and confirmatory cellular reporter gene assays, we identified four novel PXR antagonists and a structurally related agonist with a common phenylaminobenzosuberone scaffold. Further characterization using biochemical ligand binding and cellular protein interaction assays classified the novel compounds as mixed competitive/noncompetitive, passive antagonists, which bind PXR directly and disrupt its interaction with coregulatory proteins. Expression analysis of prototypical PXR target genes ABCB1 and CYP3A4 in LS174T colorectal cancer cells and HepaRG hepatocytes revealed novel antagonists as selective receptor modulators, which showed gene- and tissue-specific effects. These results demonstrate the possibility of dual PXR and protein kinase inhibitors, which might represent added value in cancer therapy.

Analysis of human Tribbles 2 (TRIB2) pseudokinase.

Human Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a broad human protein interactome, including the well-studied AKT, C/EBPα and MAPK modules. Several lines of evidence indicate that human TRIB2 promotes cell survival and drug-resistance in solid tumors and blood cancers and is therefore of interest as a potential therapeutic target, although its physiological functions remain relatively poorly understood. The unique TRIB2 pseudokinase domain lacks the canonical 'DFG' motif, and subsequently possesses very low affinity for ATP in both the presence and absence of metal ions. However, TRIB2 also contains a unique cysteine-rich αC-helix, which interacts with a conserved peptide motif in its own carboxyl-terminal tail. This regulatory flanking region drives regulated interactions with distinct E3 ubiquitin ligases that serve to control the stability and turnover of TRIB2 client proteins. TRIB2 is also a low-affinity target of several known small-molecule protein kinase inhibitors, which were originally identified using purified recombinant TRIB2 proteins and a thermal shift assay. In this chapter, we discuss laboratory-based procedures for purification, stabilization and analysis of human TRIB2, including screening procedures that can be used for the identification of both reversible and covalent small molecule ligands.

Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy.

Cancer is the second leading cause of death worldwide responsible for about 10 million deaths per year. To date several approaches have been developed to treat this deadly disease including surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy, and synthetic lethality. The targeted therapy refers to targeting only specific proteins or enzymes that are dysregulated in cancer rather than killing all rapidly dividing cells, has gained much attention in the recent past. Kinase inhibition is one of the most successful approaches in targeted therapy. As of 30 March 2021, FDA has approved 65 small molecule protein kinase inhibitors and most of them are for cancer therapy. Interestingly, several kinase inhibitors contain one or more fused heterocycles as part of their structures. Pyrrolo[2,1-f][1,2,4]triazine is one the most interesting fused heterocycle that is an integral part of several kinase inhibitors and nucleoside drugs viz. avapritinib and remdesivir. This review articles focus on the recent advances made in the development of kinase inhibitors containing pyrrolo[2,1-f][1,2,4]triazine scaffold.

Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes.

Small-molecule protein kinase inhibitors are used for the treatment of various diseases. Although their effect(s) on the respective kinase are generally quite well understood, surprisingly, their interaction with membranes is only barely investigated; even though these drugs necessarily come into contact with the plasma and intracellular membranes. Using biophysical methods such as NMR, ESR, and fluorescence spectroscopy in combination with lipid vesicles, we studied the membrane interaction of the kinase inhibitors sunitinib, erlotinib, idelalisib, and lenvatinib; these drugs are characterized by medium log p values, a parameter reflecting the overall hydrophobicity of the molecules, which is one important parameter to predict the interaction with lipid membranes. While all four molecules tend to embed in a similar region of the lipid membrane, their presence has different impacts on membrane structure and dynamics. Most notably, sunitinib, exhibiting the lowest log p value of the four inhibitors, effectively influences membrane integrity, while the others do not. This shows that the estimation of the effect of drug molecules on lipid membranes can be rather complex. In this context, experimental studies on lipid membranes are necessary to (i) identify drugs that may disturb membranes and (ii) characterize drug–membrane interactions on a molecular level. Such knowledge is important for understanding the efficacy and potential side effects of respective drugs.

Abstract 2890: Mitotic inhibitors suppresses tumor formation and metastasis of triple negative breast cancer (TNBC)

Abstract Cell division cycle 20 (Cdc20) is the main activator of the anaphase-promoting complex (APC/C) and is essential in mitosis regulation. Recently, several papers reported that Cdc20 is highly conserved in various human cancers such as pancreatic, prostate, and lung cancers yet its relation to breast cancer is unclear. Here, we found that Cdc20 gene was highly expressed in three different TNBC cell lines among the mitosis regulator genes through the National Center for Biotechnology Information (NCBI). High Cdc20 level is positively correlated with metastasis-free patient survival and relapse-free patient survival in breast cancer patient database. We also checked that Cdc20 is highly conserved in all TNBC cell lines compared to other subtypes of breast cancer cell lines and the knockdown of this gene decreased cell growth and invasion in TNBC. Furthermore, we investigated that the mitosis-related small molecule protein kinase inhibitors such as VX-680, ZM447439, BI2536, and apcin also inhibit tumor cell proliferation, migration, and invasion. In conclusion, Cdc20 has an important role in TNBC cell growth and metastasis. Cdc20 might serve as a potential marker of disease progression and as a principal potential therapeutic target. Also, mitosis-related protein kinase inhibitors are additional potential therapy to suppress cancer cell progression and invasion in TNBC effectively. Citation Format: Chaeun Song, SeungBaek Lee. Mitotic inhibitors suppresses tumor formation and metastasis of triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2890.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 in Healthy Subjects: A Placebo-Controlled, Randomized Phase 1 Study.

PurposeATI-450 is an oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) inflammatory signaling pathway. This phase 1, single and multiple ascending dose (SAD, MAD) study evaluated ATI-450 safety, tolerability, pharmacokinetics, and pharmacodynamics.Patients and MethodsHealthy adults were randomly assigned to SAD (10, 30, 50, 100 mg; n=24) and MAD (10, 30, 50 mg twice daily [BID] for 7 days; n=24) cohorts of ATI-450 or placebo (n=14). Safety and tolerability were evaluated through clinical and laboratory assessments. Pharmacokinetic parameters were evaluated in plasma samples; pharmacodynamic assessments included quantification of cytokine levels (tumor necrosis factor α [TNF-α], interleukin [IL]-1β, IL-6, IL-8) and phosphorylation of the MK2 downstream substrate, heat shock protein 27 (p-HSP27).ResultsThe most common adverse events were headache (10/48, 20.8%), dizziness (6/48, 12.5%), upper respiratory tract infection (3/48, 6.3%), and constipation (3/48, 6.3%). Pharmacokinetics were dose-proportional, with a terminal half-life of 9‒12 hours in the MAD cohorts on day 7. Dose- and concentration-dependent inhibition of ex vivo stimulated cytokines and target biomarker was observed. On day 7, patients in the 50 mg BID dose cohort recorded mean trough drug levels that were 1.4, 2.2, 2.3, and 2.4 times greater than the IC80 for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. Mean Cmax was 3.5, 5.4, 5.6, and 6.0 times greater than the IC80 for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. IL-6 inhibition >50% was noted for part of the dosing interval.ConclusionATI-450 was well tolerated at the doses investigated, exhibited dose- and time-independent (ie, linear) pharmacokinetics, and dose-related pharmacodynamic effects. These results support further study of ATI-450 in immunoinflammatory diseases in phase 2 trials.

Kinase drug discovery 20 years after imatinib: progress and future directions.

Protein kinases regulate nearly all aspects of cell life, and alterations in their expression, or mutations in their genes, cause cancer and other diseases. Here, we review the remarkable progress made over the past 20 years in improving the potency and specificity of small-molecule inhibitors of protein and lipid kinases, resulting in the approval of more than 70 new drugs since imatinib was approved in 2001. These compounds have had a significant impact on the way in which we now treat cancers and non-cancerous conditions. We discuss how the challenge of drug resistance to kinase inhibitors is being met and the future of kinase drug discovery.

Rational Design of Potential Bcr-Abl Tyrosine Kinase Inhibitors by the Methods of Molecular Modeling

Discovery of the nature of inhibiting cancer processes by small organic molecules has changed the principles of the development of drug compounds for antitumor therapy. Recent achievements in this area are associated with the design of small-molecule protein kinase inhibitors, organic compounds exhibiting directed pathogenetic action. In this study, in silico design of 38 potential anti-cancer compounds with multikinase profile was carried out based on the derivatives of 2-arylaminopyrimidine. Evaluation of inhibitory activity potential of these compounds against the native and mutant (T315I) forms of Bcr-Abl tyrosine kinase, an enzyme that plays a key role in the pathogenesis of chronic myeloid leukemia characterized by uncontrolled growth myeloid cells in peripheral blood and bone marrow, was performed using molecular modeling tools. As a result, 5 top-ranking compounds that exhibit, according to the calculated data, a high-affinity binding to the native and mutant Bcr-Abl tyrosine kinase were identified. The designed compounds were shown to form good scaffolds for the development of novel potent antitumor drugs.

Binding of the small-molecule kinase inhibitor ruxolitinib to membranes does not disturb membrane integrity

Ruxolitinib is a small-molecule protein kinase inhibitor, which is used as a therapeutic agent against several diseases. Due to its anti-inflammatory impact, ruxolitinib has also been considered recently for usage in the treatment of Covid-19. While the specific effects of ruxolitinib on Janus kinases (JAK) is comparatively well investigated, its (unspecific) impact on membranes has not been studied in detail so far. Therefore, we characterized the interaction of this drug with lipid membranes employing different biophysical approaches. Ruxolitinib incorporates into the glycerol region of lipid membranes causing an increase in disorder of the lipid chains. This binding, however, has only marginal influence on the structure and integrity of membranes as found by leakage and permeation assays.

Assessment of acute kidney injury related to small-molecule protein kinase inhibitors using the FDA adverse event reporting system

Small-molecule protein kinase inhibitors (PKIs) have substantially improved clinical outcomes of various diseases. However, some studies suggested these agents might induce acute kidney injury (AKI). This study was designed to comprehensively assess the adverse events of AKI in real-world patients receiving small-molecule PKIs using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The FAERS data between 2004 and 2019 were extracted to describe the characteristics of AKI cases after the use of small-molecule PKIs approved by the FDA. The reporting odds ratio (ROR) with 95% confidence interval (CI) for AKI was calculated for each small-molecule PKI agent. A disproportionality signal was defined when the lower limit of 95% CI > 1. Among the 462,020 adverse event reports for small-molecule PKIs, 9970 (2.16%) were identified as AKI cases. The median AKI onset time was 32 (interquartile range 11-124) days after the initiation of small-molecule PKI treatment. A total of 61.38% and 26.04% of AKI cases resulted in hospitalization and death, respectively. Based on RORs, 14 of 52 small-molecule PKIs yielded disproportionality signals for AKI, including six VEGFR inhibitors, three mTOR inhibitors and five small-molecule PKIs with other targets. The agents with the highest AKI RORs were entrectinib (ROR 6.40, 95% CI 2.23, 18.34), sirolimus (ROR 3.76, 95% CI 3.45, 4.09), and cobimetinib (ROR 3.40, 95% CI 2.69, 4.28). Analysis of the FAERS data helped identify the small-molecule PKIs that were most frequently reported for AKI. Further investigations are needed to confirm these potential risks.