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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The function of the protein kinases is to provide a mechanism for transmitting information from a factor (e.g., a growth factor) outside a cell to the interior of the cell without the initiating factor crossing the cell membrane. Large proteins such as growth factors, unlike small molecules, would normally have difficulties crossing cell membranes unless a special transport mechanism exists. Therefore, through this mechanism, protein kinases help to regulate cellular functions such as proliferation, cell-matrix adhesion, cell–cell adhesion, movement, apoptosis control, transcription, and membrane transport.
Fetal Growth Factors*
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
Philip A. Gruppuso, Thomas R. Curran, Roderick I. Bahner
Evidence for involvement of phosphorylation cascades in EGF action has come from studies showing EGF activation of serine/threonine kinases,59 including casein kinase II, raf, and the mitogen activated protein (MAP) kinase. The substrates for these kinases are diverse. They include transcription factors, enzymes which modify DNA topology, cytostructural proteins, and regulators of protein synthesis. In a number of cases kinase activation is coupled to downstream activation of yet another kinase. Importantly, such cascades provide for signal amplification at each phosphorylation step.
Principles of systemic treatment
Published in Peter Hoskin, Peter Ostler, Clinical Oncology, 2020
Communication within and between cells is mediated by extensive biochemical interactions triggered by cell surface receptors. Tyrosine kinases are frequent components of these cascades, particularly those related to the epidermal growth control receptor (EGFR) and angiogenesis (VEGF [vascular endothelial growth factor] and PDGF [platelet-derived growth factor]). Drugs which act primarily through the inhibition of tyrosine kinases include imatinib, gefitinib, sorafenib and sunitinib.
Discovery of new symmetrical and asymmetrical nitrile-containing 1,4-dihydropyridine derivatives as dual kinases and P-glycoprotein inhibitors: synthesis, in vitro assays, and in silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mohamed H. Saad, Tarek F. El-Moselhy, Nabaweya S, El-Din, Ahmed B. M. Mehany, Amany Belal, Mohammed A. S. Abourehab, Haytham O. Tawfik, Mervat H. El-Hamamsy
Cancer is still the second leading cause of death worldwide, despite advances in its treatment and prevention. However, the effectiveness of cancer treatment in the twenty-first century is still a worry, and new and safer anticancer drugs with a broader range of cytotoxicity to tumour cells need to be researched.1,2 Many types of cancers arise as a result of the ability of cells to proliferate indefinitely and their inherent resistance to apoptosis. Tumour cells have the potential to stimulate their self-proliferation via biological pathways, including meiotic cell division, which contributes to carcinogenesis.3,4 Relying on new evidence, kinases proteins such as receptor tyrosine kinases (RTKs) and cyclin-dependent kinases (CDKs) are the most extensively studied targets in diverse carcinogenic signalling pathways because they have been involved in highly conserved physiological processes such as cell proliferation, mitosis, and cell division.5,6 Aberrant or excessive production of these proteins disrupts the normal regulation of the cell cycle, which is seen in a variety of cancers. Accordingly, kinases inhibitors interfere directly with biological processes, preventing excessive cell proliferation and tumour progression.7,8 It was found that 1,4-dihydropyridines (1,4-DHPs) could be promising RTK and CDK inhibitors.9–11
Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Asmaa A. Mandour, Ibrahim F. Nassar, Mohammed T. Abdel Aal, Mahmoud A. E. Shahin, Wael A. El-Sayed, Maghawry Hegazy, Amr Mohamed Yehia, Ahmed Ismail, Mohamed Hagras, Eslam B. Elkaeed, Hanan M. Refaat, Nasser S. M. Ismail
Protein kinases represent a large group of structurally related enzymes that are essential and regulate cell cycle progression involved in cell division1–3. Cyclin-dependent kinases (CDKs) are serine-threonine kinases responsible for cell cycle regulation and cell differentiation2. Cyclin-dependent kinases (CDK) are mainly responsible for the phosphorylation process of proteins4–6. Cyclin is the regulatory protein bound by CDK leading to ATP binding region modification2. CDKs in absence of cyclin have less activity where the activation loop (known as T-loop) blocks the cleft, and the key amino acid residues are not optimally positioned for ATP binding2. CDK2 has a catalytic effect in cyclin-dependent protein kinase complex7,8. Protein phosphorylation has a critical role in cellular function regulation. This essential role during the cell cycle could be altered in tumour cells7–11. Alteration in kinases may lead to the development of many diseases, including cancer. Hence, the control of CDK dependent cell cycle is essential for tumour progression management. Where overexpression of CDK enzymes occurs in cancer2. As uncontrolled CDK2 activation in human cancer is associated with overexpression of cyclins A and E in many human cancers12. Thus, CDKs are considered critical targets for the development of novel anticancer drugs9,10.
An update of targeted therapeutic options for primary Sjögren syndrome: current status and future development
Published in Expert Opinion on Pharmacotherapy, 2021
Soledad Retamozo, Antoni Sisó-Almirall, Alejandra Flores-Chávez, Manuel Ramos-Casals, Pilar Brito-Zerón
Kinases are a group of enzymes that transfer a phosphate group to a protein, playing a key role in maintaining cellular function by turning protein function on, while other enzymes (phosphatases) reverse this action [77]. Approximately 538 known kinases are encoded in the human genome, which are subdivided into seven families of typical and seven families of atypical protein kinases. One of the more recent therapeutic approaches to control autoimmune and inflammatory responses has been to target the activity of kinases [78]. Inhibition of kinases may be achieved by means of small molecules designed to interfere with the enzyme regardless of its cellular location, or by monoclonal antibodies (mAbs) targeting kinase receptors located at the cell surface. Small-molecule inhibitors are molecules ≤500 Da in size (the names of the molecules use the stem ‘-ib’ at the end) [79], while the names of mAbs use the general stem ‘-mab,’ with specific sub-stems according to the source (‘-ximab’ for chimeric mAbs, ‘zumab’ for humanized mAbs, and ‘-mumab’ for fully human mAbs) [80].