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Drug discovery and development: From gene to drug. The four key steps of cancer drug discovery that are covered in this review are highlighted in the centre. ‘Reverse translation’ from the clinic back to the laboratory is covered under the target validation and selection section. Modified with permission from (Collins and Workman, 2006).
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The discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic chemotherapy to a personalised medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular ge...
Citations
... [5][6][7] Consequently, the quest for novel small molecules with potent and selective antitumor potential is still a significant challenge for medicinal chemistry scientists. [8][9][10][11] One effective strategy in cancer treatment involves leveraging the heightened rate of cell proliferation exhibited by cancer cells, which is characterized by a majority of DNA-managing enzymes like topoisomerase (Topo). [12] A considerable number of anticancer agents work by disrupting DNA biosynthesis, interacting directly with DNA, or impeding proper DNA relaxation by inhibiting topoisomerases. ...
... Two molecular docking processes were applied to describe the Topo I and Topo II (PDB IDs: 1T8I and 3QX3), respectively, inhibitory potentials of the novel synthesized tetrahydrobenzo[b]thiophene derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The best candidate 3 toward both Topo I and Topo II receptors was selected to clarify its binding modes and compare it to camptothecin and doxorubicin, respectively, as reference drugs. ...
... IR (KBr, υ/ cm -1 ): 3398 (NH), 2932, 2833 (C-H aliph. ), 1700 (C═O (ester) ). 1 The IC 50 of the tetrahydrobenzo[b]thiophene derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) was determined by MTT assay. [57,58] ...
A series of tetrahydrobenzo[b]thiophene derivatives was designed and synthesized as dual topoisomerase (Topo) I/II inhibitors implicating potential DNA intercalation. Ethyl-2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylate (1) was prepared by modification of the Gewald reaction procedure using a Fe 2 O 3 nanocatalyst and then it was used as a building block for the synthesis of tetrahydrobenzo[b]thiophene candidates (2-14). Interestingly, compound 14 showed the best cytotoxic potential against hepatocellular, colorectal, and breast cancer cell lines (IC 50 = 7.79, 8.10, and 3.53 µM), respectively, surpassing doxorubicin at breast cancer (IC 50 = 4.17 µM). Meanwhile, the Topo I and II inhibition assay displayed that compound 3 could exhibit the best inhibitory potential among the investigated candidates (IC 50 = 25.26 and 10.01 nM), respectively, in comparison to camptothecin (IC 50 = 28.34 nM) and doxorubicin (IC 50 = 11.01 nM), as reference standards. In addition, the DNA intercalation assay showed that compound 14 could display the best binding affinity with an IC 50 value of 77.82 µM in comparison to doxorubicin (IC 50 = 58.03 µM). Furthermore, cell cycle and apoptosis analyses described that compound 3 prompts the G1 phase arrest in michigan cancer foundation-7 cancer cells and increases the apoptosis ratio by 29.31% with respect to untreated cells (2.25%). Additionally, the conducted molecular docking assured the promising binding of the investigated members toward Topo I and II with potential DNA intercalation. Accordingly, the synthesized compounds could be treated as promising anticancer candidates for future optimization.
... Chemical and small-molecule medications are a cornerstone of cancer treatment. These drugs, designed to interact with specific molecular targets within cancer cells or related pathways, offer a broad range of therapeutic approaches [83]. Traditional chemotherapy drugs are small molecules that interfere with cell division. ...
Fibrosarcoma represents a significant challenge in oncology, characterized by high in-vasiveness and a poor prognosis. Gelatinases, particularly matrix metalloproteinases MMP-2 and MMP-9, play a pivotal role in the degradation of the extracellular matrix, facilitating tumor invasion and metastasis. Inhibiting these enzymes has emerged as a promising therapeutic strategy. This review evaluates the progress in the development and therapeutic potential of gelatinase inhibitors as treatments for fibrosarcoma over the last decade, highlighting molecular mechanisms and future directions. A comprehensive literature review was conducted, focusing on studies published from 2013 to 2023. Research articles and review papers relevant to gelatinase inhibition and fibrosarcoma were examined to assess the efficacy and mechanisms of gelatinase inhibitors. Gelatinase inhibitors have shown the potential to reduce tumor progression, invasion, and metastasis in fibrosarcoma. Clinical trials, although limited, have indicated that these inhibitors can be effectively integrated into existing therapeutic regimens, offering a reduction in metastatic spread and potentially improving patient survival rates. Mechanistic studies suggest that the inhibition of MMP-2 and MMP-9 disrupts critical pathways involved in tumor growth and cell invasion. Gelatinase inhibition represents a viable and promising approach to fibrosarcoma treatment. Future research should focus on developing more specific inhibitors, understanding long-term outcomes, and integrating gelatinase inhibition into multimodal treatment strategies to enhance efficacy.
... Third, due to greater oral availability and lack of immunogenicity, most patients are more tolerant to small molecule drugs 12 . Fourth, in consideration of the economy, the cost to manufacture, store, and transport small molecule drugs is generally cheaper because of the stable structure 13 . In this review we summarized the current advances of small molecule drugs targeting immune checkpoints (Table 1 & Figure 1) and highlighted the specific underlying mechanism and interaction residues of small molecule drugs with immune checkpoints. ...
Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration.
... In most developing nations, front-line chemotherapy is a standard set for treating benign or advanced cancers, as it is relatively cost-effective. [1][2][3][4] In comparison, precision medicine, offers more targeted therapy with better outcomes and lesser side effects, but is cost-prohibitive. 1 Therefore, it is imperative to discover better front-line chemotherapy to ameliorate cancer. Among the front-line chemotherapy, the microtubule inhibitor Paclitaxel is administered to manage a wide range of cancers. 2 Paclitaxel binds to the taxol binding site in the α-Paclitaxel binds to the taxol binding site in the 5" thor><Year>2020</Year><RecNum>725</ RecNum><DisplayText>. 2,3 The disruption in tubulin homeostasis triggers cell death termed as mitotic catastrophe. ...
... [1][2][3][4] In comparison, precision medicine, offers more targeted therapy with better outcomes and lesser side effects, but is cost-prohibitive. 1 Therefore, it is imperative to discover better front-line chemotherapy to ameliorate cancer. Among the front-line chemotherapy, the microtubule inhibitor Paclitaxel is administered to manage a wide range of cancers. 2 Paclitaxel binds to the taxol binding site in the α-Paclitaxel binds to the taxol binding site in the 5" thor><Year>2020</Year><RecNum>725</ RecNum><DisplayText>. 2,3 The disruption in tubulin homeostasis triggers cell death termed as mitotic catastrophe. ...
... 49 Some compounds have good binding affinity with target Shoko and Mandivenga 5 receptors but, however, fail in clinical trials at advanced stages of drug discovery due to their lack of drug-likeness properties. 50 The desirable properties are derived from the Lipinski RO5 which states that drug-like compounds have Log P ⩽ 5, number of hydrogen bond acceptors ⩽10, the number of hydrogen bond donors' ⩽5 and a molecular weight ⩽500. 51 The 34 S fruticosa ligands that demonstrated good binding affinity with SmSULT were analysed for drug-likeness using DataWarrior to assess their physiochemical properties. ...
Schistosomiasis, otherwise known as bilharzia or snail fever, is a disease that usually affects poor people and people exposed to poor sanitation. The disease affects over 200 million people worldwide annually. Schistosomiasis has been treated using a single drug, praziquantel, since the 1970s and this is resulting in schistosomes becoming resistant. Therefore, there is an urgent need to develop new antischistosoma drugs and vaccines. This study focuses on identifying potential antischistosomal compounds from the plant Salvia fruticosa. We virtually screened a library of 163 S fruticosa compounds by docking against Schistosoma mansoni sulfotransferase (SmSULT) using the PyRx software. Docking scores ranged from −4.7 to −9.3 kcal/mol. Compounds with binding affinity of −7.6 or stronger were subjected to drug-likeness assessments using the DataWarrior software. We also employed the PAINS removal tool to filter off false-positive results. Twelve compounds passed the drug-likeness screen, and these were subjected to in silico toxicity predictions to determine their mutagenic, tumorigenic and reproductive potential. Seven compounds were predicted to be nontoxic. After considering the toxicity analysis results and drug scores of the compounds, we identified rosmarinic acid and hispidulin as qualifying for further evaluation as potential drugs against schistosomiasis. Free energy calculations using the fastDRH webserver and molecular dynamics simulations using CABS-flex showed that the receptor-ligand complexes for the 2 lead compounds are stable under physiological conditions. We recommend that rosmarinic acid and hispidulin be used as hit compounds for the development of potential antischistosomal drugs.
... This would open up the possibility of using a broad range of structurally diverse compounds as inducers, including probes, markers, inhibitors, cofactors, etc., working in biological systems, [23,24] nutritional supplements, food preservatives, additives, and flavorings used in the food industry, [25] and small-molecule medicinal drugs. [26] A key advantage of this approach is that an ROS scavenger, such as FDA-approved N-acetyl-L-cysteine (NAC), [27] could be used to turn the gene switch off by decreasing the ROS levels in an emergency. ...
Synthetic biology aims to engineer transgene switches for precise therapeutic protein control in cell‐based gene therapies. However, off‐the‐shelf trigger‐inducible gene circuits are usually switched on by single or structurally similar molecules. This study presents a mammalian gene‐switch platform that controls therapeutic gene expression by a wide range of molecules generating low, non‐toxic levels of reactive oxygen species (ROS). In this system, KEAP1 (Kelch‐like ECH‐associated protein 1) serves as ROS sensor, regulating the translocation of NRF2 (nuclear factor erythroid 2‐related factor 2) to the nucleus, where NRF2 binds to antioxidant response elements (ARE) to activate the expression of a gene of interest. It is found that a promoter containing eight‐tandem ARE repeats is highly sensitive to the low ROS levels generated by the soluble and volatile molecules, which include food preservatives, food additives, pharmaceuticals, and signal transduction inducers. In a proof‐of‐concept study, it is shown that many of these compounds can independently trigger microencapsulated engineered cells to produce sufficient insulin to restore normoglycemia in experimental type‐1 diabetic mice. It is believed that this system greatly extends the variety of small‐molecule inducers available to drive therapeutic gene switches.
... Several anticancer drugs are available in the market, and more are in different stages of clinical trials [4]. Most of the anti-cancer drugs in clinical trials are associated with several side effects like metastasis, organ toxicity, short circulating half-life, and a tendency to induce resistance in target cells [5]. Hence, researchers all over the world to develop effective anti-cancer drugs with minimal side effects. ...
Background
Cancer is one of the most common reasons for mortality in the world. A continuous effort to develop effective anti-cancer drugs with minimum side effects has become necessary. The use of small-molecule drugs has revolutionized cancer research by inhibiting cancer cell survival and proliferation. Quinazolines are a class of bioactive heterocyclic compounds with active pharmacophores in several anti-cancer drugs. Such small molecule inhibitors obstruct the significant signals responsible for cancer cell development, thus blocking these cell signals to prevent cancer development and spread.
Objective
In the current study, novel quinazoline derivatives structurally similar to erlotinib were synthesized and explored as novel anti-cancer agents.
Methods
All the synthesized molecules were confirmed by spectroscopic techniques like 1H NMR, 13C NMR, and ESI-MS. Various techniques were applied to study the protein-drug interaction, DFT analysis, Hirshfeld surface, and target prediction. The molecules were screened in vitro for their anti-cancer properties against 60 human tumor cell lines. The growth inhibitory properties of a few compounds were studied against the MCF7 breast cancer cell line.
Results
The activity of compounds 9f, 9o, and 9s were found to be active. However, compound 9f is more active when compared with other compounds.
Conclusion
Some synthesized compounds were active against different cancer cell lines. The in-vitro study results were found to be in agreement with the predictions from in-silico data. The selected molecules were further subjected to get the possible mechanism of action against different cancer cells.
... These proteins have a molecular weight that is less than 500 daltons, which shows that they are notably smaller in size. Monoclonal antibodies have a higher molecular weight than these proteins do [18]. Due to the fact that they are so small, they are easily able to pass through the membranes of the cells in the body and may be ingested orally. ...
Cancer is a disease that can be found in every nation on the earth, and it is the cause of about one death out of every six that takes
place everywhere. It is a public health issue. The treatment of cancer has been shown to be a difficult effort due to its complexity.
Surgical operations, chemotherapy, and radiation therapy are examples of some of the traditional therapeutic approaches that have
been used for a significant amount of time. Recent scientific breakthroughs, on the other hand, have led to the development of
novel therapeutic methods. These include stem cell therapy, targeted therapy, ablation therapy, nanoparticles, naturally occurring
antioxidants, radionics, chemodynamic therapy, sonodynamic therapy, and therapies based on ferroptosis. Surgical operations,
chemotherapy, and radiation therapy are examples of conventional therapeutic approaches that have been used for a considerable
amount of time. At the present, the most important objective of research efforts in the field of oncology is to create a nanomedicine
for the treatment of cancer that is not only completely safe but also very effective.
... The search for novel classes of anti-cancer medications focuses on enhancing cancer patients' treatment efficacy and survival rates. The usual "one-size-fits-all" approach of standard non-targeting medicines damages healthy cells and may not benefit all patients [5,6]. Because cancer is a major focus of the precision medicine program, customized therapy approaches targeted at optimizing outcomes based on individual variability in genetic profile, lifestyle, and focus of the precision medicine program, customized therapy approaches targeted at optimizing outcomes based on individual variability in genetic profile, lifestyle, and environmental factors are gaining popularity [7]. ...
A new class of benzimidazole-based derivatives (4a–j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a–j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.
... These small molecules are often called anti-inflammatory drugs and can be divided into two categories by their chemical structures. They can either be steroidal, like Glucocorticoids, or nonsteroidal agents, like JAK and PDE4 inhibitors [9]. These drugs often target chronic inflammation and autoimmune diseases such as multiple sclerosis, chronic obstructive pulmonary disease, inflammatory bowel diseases, psoriasis, and rheumatoid arthritis [6]. ...
In the most recent century, small molecule drugs have become prominent in treating different illnesses and diseases. These small molecule drugs, ranging between 0.1 and 1 kDa in size, have been specifically chemically synthesized not to trigger immune responses. In addition to their nonimmunogenic nature, small molecules tend to possess a low molecular weight and a well-defined structure. They are process-independent, stable, and completely characterizable.
