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Tyrosine Kinase Inhibitors in Cancer
Intracellular protein tyrosine kinases, including Abelson (Abl), Src, JNK and many others, play a pivotal role in signal transduction pathways and cancer development, being highly activated in malignant tumor cells, but having very low activity and expression in normal cells. Consequently, in the last thirty years, many small molecule tyrosine kinase inhibitors (TKIs) have entered in clinical trials and were approved to treat hematologic and non-hematologic tumors, thus improving cancer treatment. In particular, the greatest progress has been made with the use of TKIs in the treatment of chronic myeloid leukemia (CML).
1. Introduction of Tyrosine Kinase Inhibitors
Intracellular protein tyrosine kinases, including Abelson (Abl), Src, JNK and many others, play a pivotal role in signal transduction pathways and cancer development, being highly activated in malignant tumor cells, but having very low activity and expression in normal cells . Consequently, in the last thirty years, many small molecule tyrosine kinase inhibitors (TKIs) have entered in clinical trials and were approved to treat hematologic and non-hematologic tumors, thus improving cancer treatment. The majority of these molecules are ATP-competitive inhibitors and are not selective, acting also on receptor tyrosine kinases (in particular, platelet-derived growth factor receptor, PDGFR, and vascular endothelial growth receptor, VEGFR) or other intracellular kinases with different selectivity and potency. Unfortunately, all of these new compounds presented sub-optimal properties such as poor solubility (very high pH-dependent solubility), low oral bioavailability and severe adverse effects, which limited their clinical application; in addition, the onset of resistance became the biggest obstacle in clinical application for some of the new molecules (in particular for Imatinib,Figure 1).
Consequently, in recent years many efforts have been made to find new molecules (e.g., Asciminib, Flumatinib; Figure 1) active on resistant CML (in particular on T315I mutation), for the treatment of different diseases (e.g., Ruxolitinib; Figure 1) currently without an effective therapy. In Table 1, selected TKIs (the most important for CML treatment and more recent and innovative than other ones) and their applications are reported. Issues related to solubility and resistance onset could be solved using safe and efficient delivery vehicles, that could improve the therapeutic efficacy, minimize toxicity, ameliorate tumor targetability and decrease drug resistance .
Consequently, in recent years many efforts have been made to find new molecules (e.g., Asciminib, Flumatinib;Figure 1) active on resistant CML (in particular on T315I mutation), for the treatment of different diseases (e.g., Ruxolitinib;Figure 1) currently without an effective therapy. InTable 1, selected TKIs (the most important for CML treatment and more recent and innovative than other ones) and their applications are reported. Issues related to solubility and resistance onset could be solved using safe and efficient delivery vehicles, that could improve the therapeutic efficacy, minimize toxicity, ameliorate tumor targetability and decrease drug resistance .
|Compound||Target||Number of Clinical Trials||Diseases||FDA Approval|
|Imatinib||Abl, PDGFR, Kit||754||CML, GIST, GVHD, many hematological and solid tumors||2001|
|Dasatinib||Abl, PDGFR, Kit, Src||320||CML, ALL, lymphoma, NSCLC and others solid tumors||2006|
|Nilotinib||Abl, PDGFR, c-Kit, LCK, EPHA3, EPHA8, DDR1, DDR2, MAPK11, ZAK||219||CML, ALL, GIST||2007|
|Ponatinib||Abl, Src, FGFR, PDGFR, VEGFR,||67||CML, ALL||2012|
|Flumatinib||Abl, PDGFR, c-Kit, CSFR||5||CML||//|
|Sunitinib||PDGFR, Kit, FLT3, VEGFR, CSF1R||610||RCC, GIST||2006|
|Sorafenib||PDGFR, c-Kit, FLT3, VEGFR, B-Raf||870||RCC, liver and thyroid cancers||2007|
|Axitinib||Abl, PDGFR, VEGRF, c-Kit||161||RCC||2012|
|Ruxolitinib||JAK1, JAK2||258||Myelofibrosis, polycythemia vera, GVHD, many other different diseases||2011|
Imatinib (IM, Gleevec®, Glivec®) was approved for CML in 2001 and today represents the first-line therapy for this type of hematological tumor, being able to block phosphorylation of Bcr-Abl, a fusion protein kinase which plays a fundamental role in CML development . As IM inhibits PDGFR and c-Kit, two other transmembrane TKs, it has been approved as frontline therapy for: (i) gastrointestinal stromal tumors (GIST), characterized by mutated and over-expressed c-Kit or PDGFR-b ; (ii) other myeloid malignancies and hypereosinophilic syndromes and (iii) systemic mastocytosis  Most of them are obviously focused on CML, but also on solid tumors, such as acute lymphoblastic lymphoma (ALL), GIST, melanoma, sarcoma, glioblastoma and papillary thyroid cancer; interestingly, some trials concern asthma (NCT01097694), chronic graft-versus-host disease (GVHD) (NCT01862965), steroid-refractory sclerotic/fibrotic type GVHD (NCT01898377), multiple sclerosis (MS) (NCT03674099) and COVID-19 (NCT04422678), this compound having good immunosuppressive properties.
Currently, 350 clinical trials (63 in recruitment) regarding Dasatinib are focused on CML, ALL, Hodgkin and non-Hodgkin lymphoma, neck, head, breast, NSCLC, melanoma, mesothelioma, ovarian, colorectal, glioblastoma and CNS tumors (Table 1). In addition, Dasatinib, also acting on PDGFR, Kit, Src, Tek and Btk , could be useful as an immunosuppressive agent for immunological disorders . Nilotinib is currently being studied in 219 clinical trials (41 in recruitment,Table 1) to evaluate its efficacy in CML, ALL, GIST and sarcoma (soft tissue sarcoma) patients, but also Huntington’s (NCT03764215), Parkinson’s (NCT02954978) and different forms of dementia pathologies (NCT02947893, NCT04002674).
Sorafenib (Figure 1) is an approved pankinase inhibitor able to target the Ras/Raf/Mek/Erk cascade pathway, PDGFR, VEGFR1/2 and the c-Kit receptor, and to block cell proliferation of different solid tumors; in particular, hepatocellular carcinoma (HCC) . However, its long-term application in clinical practice was hampered by serious dermal toxicity and drug resistance, low water solubility and the first-pass effect  and consequent low drug concentration in tumor tissue. In addition, it can induce paradoxical activation of the MAPK pathway in both malignant and normal stromal cells  and this fact in hepatic stellate cells (HSCs) leads to their activation with consequent liver damage. Other pankinase inhibitors (e.g., Sunitinib and Axitinib;Figure 1) have been more recently approved for advanced RCC, unresectable HCC, thyroid cancer and GIST, and many other clinical trials are ongoing also on different solid tumors and leukemia types .
Seventy-six clinical trials (31 in recruitment,Table 1) focused on CML, ALL and different solid tumors (as NSCLC, GIST, glioblastoma, breast and many others) are reported for Ponatinib, (Iclusig,Figure 1) , approved in 2012 for CML treatment. In 2013, the FDA temporarily suspended Ponatinib sales because of the risk of life-threatening blood clots and severe narrowing of blood vessels, but at the end of the same year, this suspension was partially lifted.
Very recently, Novartis announced the results of a phase III ASCEMBL study (multicenter, open-label, randomized study) regarding Asciminib (ABL001,Figure 1), a new Abl allosteric inhibitor; the study evaluated Asciminib administration in adult patients with Philadelphia chromosome-positive CML in chronic phase, previously treated with two or more TKIs for 24 weeks . On the basis of these interesting results, the FDA has granted Fast Track designation for Asciminib. Now, 14 clinical trials (two of them completed,Table 1) are focused on this compound (alone or in association with IM or Nilotinib) for CML and other leukemic patients; only one clinical trial is focused on asthma treatment (NCT03549897).
Flumatinib (HHGV678,Figure 1) is an orally bioavailable TKI, recently approved in China ; it inhibits the wild-type and mutated Bcr-Abl, PDGFR and mast/stem cell growth factor receptor (SCFR and c-Kit). Up to date, five clinical trials (one completed,Table 1) regarding only CML are in progress.
Ruxolitinib (Jakafi,Figure 1) is a selective JAK1 and JAK2 inhibitor approved for myelofibrosis (2011), polycythemia vera (2014) and GVHD in adult and pediatric patients (2019), but now it is also under study for COVID-19 (NCT04414098, NCT04359290, NCT04348071), atopic dermatitis (NCT039208529) and vitiligo (NCT04530344) (Table 1).
Although new compounds are continuously placed on the market and many are effective against different mutations, problems regarding poor solubility, resistance and severe side effects are not completely overcome. In part, the evolutionary probability of resistance can also be overcome with the association of two or more compounds, but this approach does not seem to be conclusive; consequently, the advent of nanotechnologies seems to be of great importance. In addition, it is also possible that the administration of one single nanoparticle containing several drugs may be more effective than the administration of several nanoparticles each containing one compound .
2. Nanoparticles of Tyrosine Kinase Inhibitors
A major part of these new nanoformulations have been patented in the last ten years ; in general, IM and Dasatinib represent the most studied compounds, whereas new molecules, such as Asciminib, Axitinib and others, are less investigated. Interesting results have been obtained for Sorafenib, Ponatinib and Nilotinib, as reported below. Regarding the routes of administration, these nanocarriers are usually injected intravenously; recent reports describe alternative administration routes thorough intratecal  and subcutaneous injection .
The entry is from 10.3390/ijms22126538
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