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Nanomaterials in Chemotherapy
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
P. K. Hashim, Anjaneyulu Dirisala
A drug is defined as a natural or artificial pharmacologically active ingredient used for the detection, diagnosis, and treatment of a disease. A drug can be either hydrophobic (e.g., paclitaxel, cisplatin, and methotrexate) or hydrophilic (e.g., gemcitabine, L-asparaginase, and antibodies) depending on its aqueous solubility [1]. Also, a drug can be negatively charged (e.g., gene therapeutics such as DNA, messenger (m)RNA, and short interfering (si)RNA), positively charged (e.g., doxorubicin (DOX)), and neutral (e.g., cisplatin) based on the charged species present in the drug. A drug also can be a small molecule, which has a low molecular weight compound below 900 daltons (e.g., DOX and cisplatin), or a high molecular weight molecule (e.g., DNA, RNA, and proteins). The structural characteristics of drugs are often related to their functions. For instance, a small molecule drug usually binds to a target gene/protein as a first step in the complicated drug action mechanisms. Small molecule drugs often induce off-target adverse effects because of their lack of specificity. In contrast to small molecule drugs, macromolecule drugs (e.g., genes and proteins) typically bind to their target either expressed on the cell surface or intracellular component with high specificity, and correct or program the disease-causing elements. Advantageously, both small molecule- and macromolecule-drugs can be used for cancer therapy. Collectively, more than 150 anticancer drugs have been approved by the US Food and Drug Administration (FDA) for various types of cancer [2].
siRNA Delivery for Therapeutic Applications Using Nanoparticles
Published in Yashwant Pathak, Gene Delivery, 2022
The gene silencing mechanism is initiated by the RNAi process in which the enzyme dicer cleaves the double stranded RNAs into short double-stranded siRNAs of 21 to 25 nt [5]. The siRNA passenger strand is then unwound, and the guide strand of siRNA is loaded into the RNA-induced silencing (RISC) complex paired with the mRNA complementary sequence, causing cleavage of target mRNAs by Argonaute 2 (Ago2) (Figure 8.1). This important mechanism has allowed to open novel therapeutic approaches by designing oligonucleotide molecules through using mRNA transcripts sequences found in the existing human genomic data. Therefore, a careful sequence selection and synthesis of tailored siRNAs may have enormous repercussions in therapy, as almost all genes might be down-regulated, while splice variants, separate transcripts, or mutations might also be specifically targeted. As a consequence, this powerful approach might help circumvent the limitations exhibited by small molecule drugs in conventional cancer therapy treatments, leading to drug development processes based on gene functionality. Therefore, the development of this therapeutic strategy may have a high impact on modern medicine [5–7].
The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
From the 1960s to the end of the 1980s it was common practice to synthesize novel small-molecule organic compounds and then screen them for pharmacological activity across different therapeutic areas in various screens in a relatively nonrational manner in the hope of identifying a lead molecule. In cancer research, the screening was mainly achieved through in vitro cytotoxicity assays based on tumor cell lines originally derived from patients, and which were immortal due to the overexpression of telomerase, thus allowing indefinite cell division to occur. Although many pharmaceutical companies and academic groups developed their own screens, the National Cancer Institute (NCI) in the US set up a screen based on 60 different cell lines arranged in panels, which has become the “Gold Standard” of in vitro screens. Known as the NCI-60 Human Tumor Cell Line Screen, this resource has served the global cancer research community for nearly 30 years. It was implemented in 1990 and was originally designed to screen up to 3,000 small molecules (synthetic or purified natural products) per year for growth inhibition or killing of tumor cells. The screen is based on 60 different human tumor cell lines divided into panels representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney. The results are provided in graphical format (Figure 2.2) with horizontal bars deflecting to the right of the mean indicating a high sensitivity to the compound being tested, and a deflection to the left a low sensitivity.
Design, synthesis, and biological evaluation of potent FAK-degrading PROTACs
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Qiaohua Qin, Ruifeng Wang, Qinglin Fu, Guoqi Zhang, Tianxiao Wu, Nian Liu, Ruicheng Lv, Wenbo Yin, Yin Sun, Yixiang Sun, Dongmei Zhao, Maosheng Cheng
To date, several potent FAK inhibitors have been developed, and some of them were conducted clinical evaluation. GSK-2256098, VS-4718, PF-562271 and Defactinib are ATP-competitive inhibitors of kinase domain. GSK-2256098 is a highly selective inhibitor of FAK and has been shown to efficiently inhibit the phosphorylation of Tyr39711. VS-4718 is used to treat metastatic non-hematological malignancies, advanced non-hematological malignancies or advanced pancreatic cancer of patients in combination with gemcitabine or nabutaxel12. PF-562271 is a highly active and highly selective FAK inhibitor developed by Pfizer13. Defactinib is evaluated to treat ovarian cancer, pancreatic cancer, non-small cell lung cancer and mesothelioma in combination with checkpoint inhibitors14. As we said above, FAK exerts kinase-dependent enzymatic functions and kinase-independent scaffolding functions. The development of the small-molecule inhibitors can inhibit the enzymatic functions of FAK, but can’t prevent the kinase-independent scaffolding functions. In addition, small molecule drugs are likely to cause off-target toxicity and even drug resistance at high concentrations. In summary, it is necessary to develop a strategy against both the enzymatic functions and scaffolding functions of FAK.
Emerging drug targets for colon cancer: A preclinical assessment
Published in Expert Opinion on Therapeutic Targets, 2022
Madison M. Crutcher, Trevor R. Baybutt, Jessica S. Kopenhaver, Adam E. Snook, Scott A. Waldman
Drugs can alternatively be classified by size: small molecules and macromolecules. Small molecule drugs are compounds with a low molecular weight that enter cells and interact with the cytoplasmic domain of cell-surface receptors and intracellular signaling molecules. Small molecules have well-established development paradigms, are less expensive, and are more convenient to administer than macromolecules [4]. Macromolecules are typically biologics and include monoclonal antibodies, polypeptides, antibody-drug conjugates, and nucleic acids. For extracellular targets, such as cell surface receptors or membrane-bound sites on cancer cells, therapeutic antibodies often directly regulate downstream cell cycle progression and cell death. These larger molecules can only act on the cell surface or on secreted molecules due to their inability to pass through the cell membrane. In addition, certain monoclonal antibodies work on cells other than cancer cells, such as immune cells, to restore stalled antitumor immune responses [5]. The first targeted agent for CRC was cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR) that was approved by the FDA in 2004, with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), approved later that year. While these relatively few available targeted drugs have impacted survival in CRC, additional targets and therapies need to be identified.
Considerations related to comparative clinical studies for biosimilars
Published in Expert Opinion on Drug Safety, 2021
Anurag S. Rathore, James G. Stevenson, Hemlata Chhabra
A biosimilar is a biological product that is claimed to be highly similar to an already approved reference product. The differences between small molecule drugs and biologics led to the need for new regulations for biosimilar approval [3]. The paramount objective of these regulatory guidelines is to ensure the quality, safety, and efficacy of biosimilars compared to the reference product. The EMA was the first organization to establish a regulatory framework for the development and approval of biosimilars in 2005 [4]. The European Union has not only overarching biosimilar guidelines in place but also established different product-specific guidelines (Table 1). A number of countries including Canada, South Africa, Japan, Korea, and India have followed the WHO guidance documents as a foundation for establishing their respective national guidelines [514]. The US Food and Drug Administration has also released an extensive regulatory guidance in 2015 for the evaluation of similarity and to guide the approval of biosimilars [6]. Other specific guidelines from FDA on quality considerations and interchangeability are listed in Table 1.