Abstract
Tyrosine kinases (TK) are critical enzymes involved in cellular processes in the joints, such as proliferation, differentiation, and apoptosis. These inhibitors target key pathways involved in cartilage degeneration and inflammation, offering hope for improved management of these conditions. This review examines the role of TK inhibitors in modulating chondrocyte activity and explores their therapeutic potential in cartilage-related diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). A search has been conducted across several relevant publications using the terms cartilage regeneration, chondrocyte activity, OA, RA, and TK inhibitors in PubMed and Google Scholar to construct this review. TK inhibitors have the potential to manage inflammatory and degenerative joint disorders. Tofacitinib, gefitinib, imatinib and other TK inhibitors have anti-inflammatory effects through various pathways, aiding in treating cartilage diseases. Tofacitinib and baricitinib are already approved for RA, while other TK inhibitors are under continuous investigation for approval in RA and OA. Nonetheless, certain obstacles like serious side effects, limited joint-specificity, and inadequate clinical research impede their utilization. Despite these challenges, TK inhibitors signify a promising treatment strategy for joint diseases, presenting the potential to improve disease management strategies and promote cartilage regeneration.
-
Key words: Arthritis, rheumatoid · Cartilage diseases · Chondrocytes · Osteoarthritis · Tyrosine kinase inhibitors
GRAPHICAL ABSTRACT
INTRODUCTION
Cartilage is a connective tissue that envelops the ends of articulating bones. Once damaged, joints reveal limited regenerative ability and a difficult repair process due to their avascular nature, absence of lymphatic tissue, and lack of innervation. Additionally, the low mitotic activity of chondrocytes, further complicates regeneration.[
1,
2]
Chondrocytes are the primary cell type dispersed within the extracellular matrix (ECM) of cartilage and responsible for the synthesis and turnover of ECM components. Imbalance in chondrocyte function results in degenerative/ inflammatory diseases of the joints, such as osteoarthritis (OA) or rheumatoid arthritis (RA).[
3–
7] Various chemical and mechanical factors in the chondrocytes environment influence their metabolic processes. The pro-inflammatory cytokines and growth factors, which exert both anabolic and catabolic effects, are among the most significant factors.[
8]
Although many groups of medications are available for the management of OA and RA, there remains a need for additional treatment options. Firstly, many patients with active joint diseases fail to achieve full control of their condition despite receiving appropriate therapy.[
9] Secondly, the current therapies are often associated with significant side effects, which can hinder their use and reduce patient adherence to treatment protocols, ultimately leading to poor disease control. Therefore, there is a need for new medications to complement or replace existing therapies for the management of RA and OA.[
10,
11]
Tyrosine kinases (TK) are a class of enzymes that translocate phosphate groups to the tyrosine residues in the target protein to drive signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. TK signaling pathways regulate apoptosis, differentiation, and proliferation in cells, including joints. There are two types of TK inside the body: non-receptor and receptor TK.[
12]
Receptor TK are transmembrane proteins. Platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), and rearranged during transfection receptor are the most important receptor TK. Non-receptor or cytosolic TK, on the other hand, do not possess extracellular or transmembrane domains. Abelson murine leukemia virus (ABL), Src, and Janus Kinase (JAK) are parts of the non-receptor TK.[
13–
15]
Both receptor and cytosolic TKs govern chondrocyte proliferation and differentiation during cartilage formation and repair. Certain TKs have been linked with the production of inflammatory mediators, whereas others are believed to be elevated in degenerated chondrocytes in order to inhibit catabolic factors or to regulate cartilage degeneration.[
16,
17] Additionally, TK signaling is involved in maintaining cellular homeostasis by modulating apoptosis. Dysregulation of these pathways can lead to pathological conditions, including impaired cartilage regeneration, excessive inflammation, and chondrocyte apoptosis, which are collectively regarded as hallmarks of degenerative joint diseases like OA.[
18] By targeting fundamental signaling cascades that regulate cellular proliferation, differentiation, survival, and inflammation, TK inhibitors may exert a promising effect on the pathways of chondrocyte activity and cartilage regeneration, thereby suggesting their potential as useful agents for managing joint diseases.
This review explores the role of TK inhibitors in modulating chondrocyte activity and their potential as a therapeutic option for patients with RA or OA. The possible challenges and the future directions for the use of TK inhibitors in the treatment of joint diseases will also be highlighted.
METHODS
A comprehensive literature search was conducted based on relevant online publications using the terms “tyrosine kinase inhibitor,” “chondrocyte activity,” “cartilage regeneration,” “rheumatoid arthritis,” “osteoarthritis,” and related keywords up to March 2025 on PubMed and Google Scholar to construct this review. Additional articles were identified by screening the reference lists of selected papers to ensure comprehensive coverage of the topic. Eligible studies were required to investigate the effects of TKs inhibitors on chondrocyte activity or cartilage pathology in the context of RA or OA. Preclinical (in vitro and animal), case reports, and clinical studies were considered.
TK INHIBITORS
1. Mechanisms and applications
TK works through binding of adenosine triphosphate (ATP) to the kinase domain in a specific orientation, positioning its γ-phosphate group near the tyrosine residue of the substrate. The kinase catalyzes the transfer of the γ-phosphate group from ATP to the hydroxyl group of the tyrosine residue, forming a phosphotyrosine and adenosine diphosphate as a byproduct. This phosphorylation event activates or modulates the function of the substrate protein, propagating downstream signaling.[
19] TK inhibitors are small-molecule drugs that inhibit the function of TK by competitively binding to their ATP-binding sites, thereby preventing the phosphorylation of target proteins. Numerous TK inhibitors have low selectivity towards their target molecule and inhibit a wider range of TK due to the conserved structure of the ATP-binding sites. Newer TK inhibitors are known as type II inhibitors, whereas older ones are known as type I inhibitors. Type I inhibitors are characterized by their ability to adopt the Asp-Phe-Gly (DFG)-in conformation. Newer compounds with advanced structural features may achieve greater specificity for a particular TK or TK family since they bind to the inactive DFG-out conformation of kinases, which exhibits greater structural variability than the conserved active conformation bound by type I inhibitors. Consequently, it is speculated that type II inhibitors are more selective than type I inhibitors, as exemplified by quizartinib, pirtobrutinib, and repotrectinib. [
20,
21]
TK inhibitors are the most well-known pathway-directed anti-cancer agents, since their development in the early 2000s. TK inhibitors have demonstrated notable effectiveness in treating a variety of solid tumors and hematological malignancies, such as HER2 positive breast cancers, non-small cell lung cancers, gastrointestinal stromal tumors, and chronic myelogenous leukemia (CML).[
22]
Over the past few decades, basic biomedical research has shown that TK are essential for a number of specialized biological processes, including immune cell development and function, bone metabolism, platelet function, and the pathological functions of non-hematopoietic cell types. [
23–
25] As a result, TK have started to become a significant therapeutic target in non-malignant conditions such inflammatory and autoimmune diseases for example psoriasis.[
26,
27]
In cartilage disorders, articular chondrocytes undergo a phenotypic shift towards hypertrophy, leading to cartilage degradation and further exacerbation of the condition. A primary hallmark of hypertrophic chondrocytes is the over-expression of proteolytic enzymes, particularly matrix metalloproteinases (MMPs), which degrade ECM components. Seven MMPs have been shown to be expressed under varying circumstances in articular cartilage. The presence of the MMP-3, MMP-8, and MMP-9 in cartilage appears to be characteristic of pathologic circumstances only, whereas MMP-13 is most notably associated with OA. Once its expression is elevated in the joint, significant damage and destruction become imminent.[
28] TK are notably linked to chondrocyte hypertrophy (
Fig. 1).[
29–
31]
Multiple pathways are linked to chondrocyte hypertrophy occurring during bone development. Pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α, via TK, have been demonstrated to upregulate hypertrophic marker expression and downregulate SRY-box transcription factor 9 by stabilizing nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and hypoxia-inducible factor 2α.[
32] Additional pathways include mitogen-activated protein kinase (MAPK) signaling, phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt), and JAK2, which activate signal transducer and activator of transcription factor (STAT).[
33] MAPK pathway activation stimulates degradation enzymes like MMPs and aggrecanases in addition to inducing apoptosis and the production of inflammatory mediators like prostaglandins. [
34] Despite the activation of enzymes and induction of inflammation, dysregulated PI3K-Akt signaling can suppress autophagy and produce chondrocyte senescence (a state in which cells lose their ability to divide and repair cartilage).[
35] JAK/STAT pathway is also associated with inflammation, upregulation of catabolic enzymes and apoptosis. [
36,
37]
TK inhibitors have the potential to influence pathways associated with chondrocyte activity and cartilage regeneration by targeting essential signaling cascades that play a role in cellular proliferation, differentiation, survival, and inflammation. TK inhibitors have the capability to inhibit pro-inflammatory cytokine signaling, such as IL-1β and TNF-α, while also reducing the activity of catabolic enzymes like MMPs, which are responsible for cartilage degradation and are upregulated during chondrocyte hypertrophy.[
38] Chondrocytes also depend on growth factor-mediated pathways to preserve cartilage homeostasis and repair, including VEGFR, PDGFR, and FGFR. TK inhibitors control excessive or dysregulated signaling that can result in cartilage deterioration by blocking the activity of receptor TK linked to these growth factors.[
39]
The overexpression of VEGFR in the cartilage leads to angiogenesis, which is linked to inflammation and vascular invasion of immune cells.[
40] Inhibitors of TK can mitigate this overexpression, thereby aiding in the preservation of the avascular nature of healthy cartilage.[
41] By modulating PDGFR (which stimulates angiogenesis through the recruitment and proliferation of perivascular cells that support and stabilize newly formed blood vessels) and FGFR pathways, TK inhibitors can promote balanced chondrocyte proliferation and ECM production.[
25,
26]
Several TK inhibitors have been developed to target the activity of one or more protein kinases that are permanently activated due to specific mutations, particularly in cancer cells. The initial focus in the development of TK inhibitors was to create drugs with high selectivity. However, it has become evident that many inhibitors of TK act as multi-kinase inhibitors, interacting with various kinases involved in different signaling pathways, including cytokine pathways. In certain instances, this relative lack of selectivity has provided novel therapeutic opportunities, mainly in cancer treatment, where targeting multiple kinases may result in enhanced efficacy.[
42] However, in non-cancerous diseases, higher selectivity is essential to provide a greater benefit and reduce off-target effects. The United States Food and Drug Administration (FDA) has already approved many TK inhibitors for the treatment of lymphoproliferative diseases and cancers. New inhibitors are under development for psoriasis and various inflammatory conditions, including RA, Crohn’s disease, and organ transplant rejection.[
43]
In the field of joint diseases, many TKs inhibitors may show a promising effect either by targeting receptor TK (erlotinib, gefitinib, lapatinib, sunitinib, masitinib, and sorafenib) or cytoplasmic TKs (tofacitinib, baricitinib, fostamatinib, and ruxolitinib). However, imatinib, dasatinib and nilotinib could interfere with both receptor and cytoplasmic TKs. Erlotinib and gefitinib (EGFR inhibitors) appear to exert a promising effect in modulating inflammatory pathways by inhibiting TNF-α and exhibiting off-target effects on the IL-1 signaling pathway.[
44] These effects may provide potential therapeutic benefit when compared to the current biologic treatments for cartilage disease by concurrently targeting both TNF-α and IL-1, key players in inflammatory joint diseases. A case study examined the application of gefitinib in a 72-year-old woman diagnosed with stage IV non-small cell lung cancer (NSCLC) and OA. Following the administration of gefitinib, the patient experienced a significant reduction in arthritic symptoms, including pain and stiffness. However, when gefitinib was temporary discontinued due to diarrhea, arthritis symptoms were returned. Re-administration of gefitinib resulted in the restoration of symptom improvement.[
45] Sun et al. [
46] also examined the effects of gefitinib on OA. The activation of EGFR, as evidenced by EGFR phosphorylation, resulted in the degradation of joints. However, EGFR inhibition effectively prevented cartilage matrix degeneration and facilitated cartilage regeneration. These findings suggest gefitinib as a promising disease-modifying option for OA, particularly in patients with concurrent cancer or EGFR-driven pathways contributing to cartilage degradation.
In the field of RA, Ohara et al. [
47] reported that NSCLC patients treated with gefitinib rarely develop RA and are not affected by prior rheumatic manifestations. Additionally, erlotinib has shown to mitigate the severity of established collagen-induced arthritis in mouse models of RA. This is mainly performed by specific targeting synovial fibroblasts, endothelial cells, and osteoclasts, thereby reducing inflammation and reducing joint destruction.[
48]
Lapatinib, sorafenib, and dasatinib have also shown promising effects in treating RA through their ability to influence synovial fibroblasts, a key cell type involved in joint inflammation and damage. In an
in vitro study, lapatinib produced a therapeutic effect on synovial fibroblasts. Lapatinib was found to suppress MMP release from these cells, which are used for ECM degradation in RA.[
49] Furthermore, intra-articular administration of lapatinib in experimental models alleviated the symptoms of RA by suppressing synovial inflammation, pannus formation, and erosion of cartilage and bone. These findings indicate that targeting EGFR pathway with lapatinib may provide promising therapeutic approach for managing RA.[
50] Sorafenib has been shown to inhibit the proliferation of fibroblast-like synoviocytes in adjuvant arthritis by arresting G1/S cell cycle progression as well as inhibiting osteoclastogenesis. This suggests sorafenib is a potential therapeutic option for early RA treatment, where preventing excessive cellular proliferation and bone destruction is essential.[
51,
52] Dasatinib, like lapatinib and sorafenib, has been shown to reduce peri-synovial inflammation and cartilage-bone destruction in rat models, suggesting this drug as an effective therapeutic option for arthritis.[
53–
56] Unfortunately, recent clinical trials that examine the efficacy of lapatinib, sorafenib, or dasatinib on OA are absent.
Fostamatinib (spleen TK inhibitor) shows a promising role in alleviating the symptoms of OA by improving the decreased chondrocyte viability and proliferation associated with the disease. It also inhibits cell apoptosis, thereby helping to preserve chondrocyte number and function in degenerated cartilage.[
57] Additionally, fostamatinib alleviates inflammation, ECM degradation, and chondrocyte phenotype change through blocking MAPK/NF-κB pathways. In a recent clinical study, fostamatinib alleviates temporomandibular joint OA by maintaining cartilage homeostasis.[
58] Furthermore, fostamatinib has been shown to improve disease symptoms, including discomfort and fatigue, and to slow disease progression. In clinical trials, fostamatinib was reported to enhance physical activity and quality of life in patients with active RA, suggesting that it may be a valuable addition to current RA treatments. [
59,
60]
Sunitinib, an inhibitor of VEGFR and PDGFR, may provide therapeutic potential in the management of inflammatory joint diseases.
In vitro studies on a murine model demonstrated that sunitinib has significant therapeutic advantages in managing inflammatory joint diseases by inhibiting synovial angiogenesis, a major pathway involved in joint inflammation and damage.[
61] Another study demonstrated that sunitinib significantly inhibits endothelial cell migration and sprouting, which is associated with a reduction in both scratch closure (cell migration study) and sprout formation (development of new blood vessel-like structures in a three-dimensional environment).[
62]
Imatinib, a potent inhibitor of VEGFR, c-kit, ABL, and PDGFR, exhibits a beneficial anti-inflammatory effect in joint diseases. Imatinib inhibits synovial cell proliferation and promotes apoptosis, offering potential for the management of joint diseases through reduction of joint inflammation and hyperplasia.[
63] Imatinib potential to block PDGFR signaling, which is necessary for osteoblast development, could provide an additional option for preventing bone erosion in patients with RA due to suppression of osteoclastogenesis through both direct and stromal cell-mediated pathways.[
64] Case studies involving patients diagnosed with RA and CML have demonstrated successful results following imatinib administration.[
65,
66]
Masitinib, another inhibitor of TK, has shown promising results in treating RA, mainly in disease-modifying antirheumatic drug-refractory patients. Masitinib appears to be relatively well tolerated. This, along with evidence of a steady effectiveness response, indicated that masitinib is appropriate for long-term therapy regimens. As a selective inhibitor of several kinases involved in inflammation, masitinib could provide a key therapeutic option for patients with RA, particularly those who are resistant to traditional therapies.[
67]
Nilotinib (ABL and mast/stem cell growth factor receptor [c-Kit] inhibitor), may have advantageous effects for people with RA. Nonetheless, there was a greater risk of several complications, such as cardiovascular disease. Patients treated with nilotinib exhibited an imbalanced pro-inflammatory and anti-inflammatory network, which can exacerbate inflammation and promote cardiovascular complications. The available reports suggested that this pro-inflammatory condition would induce pro-atherothrombotic activation by increased lipid peroxidation, and that the genetic propensity to atherothrombosis associated with lipoxygenase 1 could contribute to the elevated frequency of vascular events in nilotinib-treated patients. Consequently, these findings resulted in limited use of nilotinib for RA patients.[
68,
69]
Tofacitinib and baricitinib (JAK inhibitors, not direct TK inhibitors) both received approval for the treatment of individuals with moderate to severe active RA. These medications may be utilized in conjunction with methotrexate or another traditional synthetic disease-modifying antirheumatic medicine, or as a single treatment after failure of traditional therapy.[
70] The effectiveness of tofacitinib and baricitinib has been validated in several clinical studies. Tofacitinib inhibits the functions of JAK1 and JAK3, with lesser effect on JAK2 and TK2. The inhibition of JAK pathways by tofacitinib diminishes the signaling from ILs and type I and II interferon receptors, leading to alterations in immunological and inflammatory responses.[
71] On the other hand, baricitinib inhibits JAK1 and JAK2, with lower efficacy on TK2 and JAK3.[
72] Baricitinib has proven effectiveness in treating RA by modulating the signaling pathways that are responsible for the inflammatory processes. [
73,
74]
In OA, tofacitinib demonstrated promising results in mitigating disease progression. A study utilized intra-articular injection of tofacitinib in animal model demonstrated a marked reduction in arthritis scores and bone disintegration. This effect was proposed to be driven by tofacitinib ability to inhibit JAK1 signaling pathway, and the suppression of pro-inflammatory cytokines such as TNF-α, and IL-6. This demonstrated the functional relationship between proinflammatory JAK1/TNF-α/IL-6 signaling and aberrant chondrocyte formation, underscoring the therapeutic potential of tofacitinib in OA.[
75]
Notwithstanding these advancements in the use of TKs inhibitors in the management of OA and RA, numerous knowledge gaps persist. A significant gap exists in direct comparative studies of various TKs inhibitors, complicating the assessment of the relative advantages of targeting specific kinases or pathways. The majority of clinical data primarily focus on JAK inhibitors, whereas other classes are predominantly in the investigational phase.
Table 1 summarizes the use of TK inhibitors in RA and OA.
The clinical development and evidence for TKs inhibitors in cartilage diseases such as RA and OA are varied. In summary, erlotinib and lapatinib demonstrate efficacy in preclinical studies, whereas gefitinib has been noted as effective in case studies for RA. However, none of these agents has advanced to clinical trials for RA or OA. Sunitinib and sorafenib exhibit a lack of both preclinical and clinical data supporting their use in OA, whereas preclinical studies in RA show promising results. Masitinib has completed phase II clinical trials for RA, with results indicating potential effectiveness.[
67] However, further studies are needed to confirm its role in OA.[
53–
56] Tofacitinib and baricitinib are approved for the treatment of RA. Tofacitinib has also shown potential in OA in preclinical studies, while baricitinib, despite its approval for RA, does not yet have published preclinical studies specifically in OA.[
73,
74] Imatinib and dasatinib have been described in case reports as potentially beneficial in RA, but there are no clinical trials or robust clinical data available for their use in OA. Nilotinib has demonstrated some effectiveness in case studies, but also revealed serious side effects, limiting its further development for these indications.[
68,
69] Fostamatinib has completed both phase II and phase III clinical trials for RA, with evidence supporting its effectiveness in inflammatory conditions. Its use in OA, however, remains investigational. [
57,
76] Ruxolitinib has reached phase II clinical trials but has not advanced further, and there are no published clinical studies for its use in OA.[
77]
FUTURE DIRECTIONS AND RECOMMENDATIONS
Although TK inhibitors have shown promising effects in the treatment of inflammatory joint disorders, many challenges need to be addressed for better therapeutic outcomes. First of all, while several TK inhibitors have shown efficacy in preclinical studies, clinical trials remain insufficient, which urges the need for a large-scale clinical study to confirm the effectiveness of these agents in RA. Likewise, few clinical studies have assessed the role of TK inhibitors in the management of OA and further trials are recommended. Secondly, TK inhibitors are associated with serious and versatile side effects, such as cardiac complications, which may limit their use, particularly those that affect multiple organs due to broad-spectrum inhibition.[
22] Suppression of multiple TK results in a variety of actions inside the body with many off-target organ effects and limited specificity on cartilage pathways. Monitoring patients receiving TK inhibitor therapy is essential, especially in long-term cases, to detect and manage potential complications. Besides, using an inhibitor that targets specifically overexpressed TK may be beneficial in this case. However, the lack of joint-specific TK inhibitor still a major concern and needs further attention. Development of cartilage-specific TK inhibitors to provide selectivity and reduce unwanted side effects is crucial driver for the use of these medications in joint diseases. Such selective inhibitors would potentially provide more localized therapeutic effects to minimize the risks associated with systemic drug action.
It is suggested that future clinical trials focus on the long-term safety and efficacy of TK inhibitors, in order to determine their effectiveness and to identify the most appropriate agent for RA or OA to be approved alongside tofacitinib and baricitinib for RA. Moreover, clinical studies focusing on the use of low-dose combination therapy of TK inhibitors and other traditional medications are recommended. The use of TK inhibitors in combination with traditional therapies may provide additional symptom relief and improve quality of life. However, the kidneys, cardiovascular system, liver, and gastrointestinal tract should be monitored closely to establish the safety of these combinations. Costs and accessibility should also be considered, as these may limit the use in some healthcare settings.
A major strength of this review is the blend of both molecular and clinical viewpoints, incorporating both receptor and non-receptor TK inhibitors while emphasizing approved and experimental medications. The review also delineates critical mechanistic developments and knowledge gaps, providing guidance for further research attempts. Nonetheless, some limits must be recognized. The predominant evidence originates from preclinical investigations, with limited data from large-scale clinical trials. The variability in study designs and endpoints presents difficulties for direct comparison and synthesis. Moreover, the extensive inclusion criteria may have resulted in diversity in the quality of the research examined. These constraints highlight the necessity for more stringent and consistent clinical research in this field.
CONCLUSIONS
TK inhibitors represent a promising therapeutic option for joint diseases like RA and OA. These drugs target key pathways involved in cartilage degeneration and inflammation, offering a significant option for improved management of these conditions. Tofacitinib and baricitinib, which have already been approved for RA, represent important advancements in this field. Other TK inhibitors, such as gefitinib and imatinib, show a promising therapeutic effect in preclinical and preliminary clinical studies. However, several challenges need to be addressed before TK inhibitors can be widely utilized for joint diseases.
DECLARATIONS
-
Acknowledgments
We express our sincere gratitude to the University of Mosul and the College of Pharmacy for their valuable guidance and support.
-
Funding
The authors received no financial support for this article.
-
Ethics approval and consent to participate
Not applicable.
-
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Fig. 1Pathways driving chondrocyte hypertrophy and the modulatory role of tyrosine kinase inhibitors.
Table 1Main tyrosine kinase inhibitors and their site of action
Table 1
|
No. |
Drug |
Group |
Enzyme inhibitor |
Use in rheumatoid arthritis |
Use in osteoarthritis |
|
1 |
Erlotinib |
Receptor TKs |
Epidermal growth factor receptor |
Preclinical, effective [47] |
No clinical studies |
|
2 |
Gefitinib |
Receptor TKs |
Epidermal growth factor receptor |
Case study, effective, no clinical trials [50] |
Case study, effective, no clinical trials [46] |
|
3 |
Lapatinib |
Receptor TKs |
Epidermal growth factor receptor |
|
|
|
4 |
Sunitinib |
Receptor TKs |
Vascular endothelial growth factor receptor and |
Preclinical, effective, |
|
|
5 |
Sorafenib |
Receptor TKs |
platelet-derived growth factor
Vascular endothelial growth factor receptor and platelet-derived growth factor |
no clinical trials [51,53,61,67] |
No clinical studies |
|
6 |
Masitinib |
Receptor TKs |
Platelet-derived growth factor and mast/stem cell growth factor receptor (CD117) |
Complete phase II clinical trials, effective [67] |
|
|
7 |
Tofacitinib |
Cytoplasmic TKs |
Janus protein kinase |
Approved [71] |
Preclinical, effective [75] |
|
8 |
Baricitinib |
Cytoplasmic TKs |
Janus protein kinase |
Approved [74] |
No clinical studies |
|
9 |
Imatinib |
Receptor+cytoplasmic |
Vascular endothelial growth factor receptor, mast/stem |
|
|
|
10 |
Dasatinib |
TKs
Receptor+cytoplasmic TKs |
cell growth factor receptor (CD117), Abelson murine leukemia virus and platelet-derived growth factor Mast/stem cell growth factor receptor (CD117), Abelson murine leukemia virus and sarcoma kinases |
Case study, effective, no clinical trials [56,63] |
No clinical studies |
|
11 |
Nilotinib |
Receptor+cytoplasmic TKs |
Mast/stem cell growth factor receptor (CD117) and Abelson murine leukemia virus |
Case study, effective, serious side effects [69] |
No clinical studies |
|
12 |
Fostamatinib |
Cytoplasmic TKs |
Spleen tyrosine kinase |
Complete phase II and III clinical trial, effective [60,76] |
Case study, effective [58] |
|
13 |
Ruxolitinib |
Cytoplasmic TKs |
Janus protein kinase |
Phase II clinical trial not advanced to phase III [77] |
No clinical studies |
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