Naslov
TYROSINE KINASE INHIBITORS (TKIs) - Challenges in anticancer therapy and regulatory perspectives

Autori
Jadrijević-Mladar Takač, Milena

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, pp prezentacija, znanstveni

Izvornik
Bioequivalence, Dissolution, Biosimilarity: From the 'Chain Bridge' to other Bridges of Pharmaceutical World / Celebi, Nevin - Ankara : Turkish Pharmaceutical Technology Scientists' Association, TUFTAD, 2015, 1-37

Skup
Bioequivalence, Dissolution, Biosimilarity: From the 'Chain Bridge' to other Bridges of Pharmaceutical World

Mjesto i datum
Antalya, Turska, 25.04.2015

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Tyrosine kinase inhibitors; anticancer therapy; regulatory perspectives; FDA; EMA

Sažetak
Protein kinases (PK) act by adding a phosphate group to a protein (phosphorylation), usually on a specific amino acid (serine, threonine or tyrosine) which often makes the protein or enzyme active. They are ubiquitous intracellular and cell surface proteins that play critical roles in cell signaling pathways involved in metabolism, injury responses, adaption, growth and differentiation. Identification of the key roles of PKs in cancer has led to extensive efforts to develop kinase inhibitors for the treatment of a wide range of cancers and they represent a major milestone in oncology. Many PKs are cell surface receptors and act to initiate an intracellular pathway of activation, after the receptor is engaged by its ligand, typically a cytokine or growth factor. Inhibitors of these kinases are called protein kinase receptor inhibitors (PKRIs). Other kinases are intracellular and take part in cell signaling. These kinases can be targeted by 'non-receptor' protein kinases. Some kinase inhibitors have specificity for multiple kinases and are called 'multi-kinase inhibitors'. The design of specific protein kinase inhibitors (PKIs) is important both, for fundamental research and for therapeutic strategies development in treatment of diseases such as cancer. The protein kinase inhibitors (PKIs) are relatively recently developed agents, among which the tyrosine kinase receptor inhibitors (TKRIs) were the initial and are the best characterized. The first approved drug in US was imatinib (2001) which is a specific inhibitor of the BCR-ABL kinase used to treat Philadelphia chromosome positive chronic lymphocytic leukemia. The introduction of imatinib was followed by more than a dozen others within the next 15 years. For instance, afatinib, erlotinib, and lapatinib has been approved for the treatment of lung cancer and lapatinib for breast cancer, and numerous new agents are in different phases of clinical trials or under regulatory review. In addition to these small molecules a several biopharmaceutical agents, i.e., monoclonal antibodies have been also approved for example in the treatment of breast cancer (pertuzumab, trastuzumab and ado-trastuzumab emtansine) and colorectal cancer (cetuximab, panitumumab). However there are differences in number of these drugs approved by FDA and EMA. A major shortcoming of all of these treatments is the development of resistance and major efforts are underway to develop alternate inhibitors that are effective against the drug-resistant tumors. Furthermore, the use of these drugs has been found to be associated with serious toxicities that affect a various vital organs including the heart. A number of TKIs are associated with three main undesirable effects regarding cardiovascular safety aspects of TKIs, namely their propensity to induce QT interval prolongation, left ventricular (LV) dysfunction and hypertension (both systemic and pulmonary). In the frame of our research project we explore the relationships between molecular descriptors (MDs), drug-likeness scores (DLs) and ADMET parameters of PTKIs, derivatives of quinoline, quinazoline, pyrido- and pyrimido-pyrimidine, in correlation studies with their experimentally obtained IC50 of target kinase activity. 1. Dassonville et al. (2007) EGFR targeting therapies: Monoclonal antibodies versus tyrosine kinase inhibitors: Similarities and differences, Criti Rev Oncol/Hemat 62 (1) p.p. 53–61. 2. Hojjat-Farsangi M (2014) Small-Molecule Inhibitors of the Receptor Tyrosine Kinases: Promising Tools for Targeted Cancer Therapies, Int. J. Mol. Sci. 15, p.p. 13768-13801.

Izvorni jezik
Engleski

Znanstvena područja
Farmacija

Napomena
BM048 - Potpora Sveučilišta u Zagrebu, biomedicinsko područje, projekt 'Istraživanje značajki inhibitora protein tirozin kinaze i histon deacetilaze u antitumorskoj terapiji' (voditelj M. Jadrijević-Mladar Takač)

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