Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 5, 2023

Cervical cancer (CC) is one of the most prevalent cancer-related pathologies in the female population. It is considered the second leading cause of cancer-related deaths in developing countries. The most important etiological factor for the development of CC is the persistent infection with high-risk human papillomavirus. HPV-oncoproteins have evolved to modulate cellular mechanisms to permit viral replication and the generation of new infectious viral particles. When the viral infection persists, there is an uncontrolled viral protein expression essential to commence and maintain the transformation of infected cells. Different cell pathways are affected during the transformation stage, including the NF-ΚB signaling pathway. NF-ΚB controls different cellular mechanisms, and its role is critical for various processes, such as immunity, inflammation, cell differentiation, growth, and survival. NF-ΚB plays a double role in the development of CC. Evidence suggests that in the early stages of viral infection, the NF-ΚB activity impairs viral transcription and is beneficial for avoiding cellular immortalization. However, in the advanced stages of cervical carcinogenesis, the activation of the NF-ΚB correlates with a poor prognosis. Here, we discuss some aspects of NF-ΚB activity during the development of CC and the use of NF-ΚB inhibitors to treat this pathology.

Background: SHP2 is a protein tyrosine phosphatase that is extensively involved in several signaling pathways related to cancer occurrence, and thus SHP2 has been proposed as an attractive target for cancer treatment. Methods: After a brief introduction of SHP2, we provided a short overview of the structure, function and regulation mechanism of SHP2 in cancer occurrence. Then, this perspective focused on the current therapeutic strategies targeting SHP2, including SHP2 PTP inhibitors, SHP2 allosteric inhibitors and SHP2-targeting PROTACs, and discussed the benefits and defects of these strategies. Finally, the opportunities and challenges were presented. Results: SHP2 regulated RAS-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 signaling pathways involved in the pathogenesis of cancer via conformations conversion. Current therapeutic strategies targeting SHP2, especially SHP2 allosteric inhibitors, hold significant potency and have broad application prospects for cancer therapy. Conclusion: In summary, SHP2 is a promising therapeutic target, and strategies targeting SHP2 offer an alternative program for cancer patients.

Amongst all types of cancers, breast cancer is recognized as the most common cancer and a principal cause of morbidity and mortality in women. Endoplasmic reticulum (ER) stress pathways are primarily activated in cancer cells and activate a signaling network called the unfolded protein response (UPR). Many tumors, by activating the UPR pathway, allow them to adapt and grow under stressful conditions. UPR is usually inactive in non-tumor cells, while it is active in tumor cells, so it is appropriate to develop new breast cancer therapies. A protein that regulates UPR is 78 KDa Glucose-Regulated Protein (GRP78). Usually, the GRP78 level in the cell is relatively low but increases significantly under stresses that affect the ER and calcium homeostasis, and increases resistance to chemotherapy. GRP78 drug suppressors could provide promising anticancer therapeutics. Therefore, understanding the molecular mechanism of GRP78 in cancer and identifying drugs that target GRP78 is essential for the treatment of breast cancer. In this review, we investigate the role of GRP78 in the pathogenesis of breast cancer.

Heterocyclic compounds are recognized to possess a high grade of structural diversity and a broad spectrum of therapeutic properties. About two-thirds of the New Chemical Entities approved by the FDA against cancer entail heterocyclic rings and are the foundation stone of medicinal chemistry. Pyrimidine being a major heterocyclic compound and a crucial base component of the genetic material, has emerged as the key structural component against cancer, the deadliest disease worldwide. Though many drugs are marketed against cancer, researchers are still investigating the more promising moieties against various malignancies due to the severity of this disease. In this review, an attempt has been made to assemble the reported literature of the previous five years on various synthetic procedures and the anti-cancer potential of various classes of fused pyrimidine analogs, which would help the researchers in designing new potent derivatives. Besides this, the review intends to focus on the comprehensive discussion on biological targets, modes of action, and structure-activity relationships of each class of fused pyrimidines as potential anticancer agents.

Background: Renal cell carcinoma (RCC) is a diverse collection of malignancies with varying histological characteristics, molecular changes, prognosis, and therapeutic response. Tivozanib was first approved in March 2021 by USFDA with the brand name Fotivda. Tivozanib hydrochloride monohydrate is an oral medication that is used to treat relapsed or refractory renal cell carcinoma. Objective: In this review, we explain renal cell carcinoma and its different types of treatment by the anti-renal carcinoma drugs. Methods: A comprehensive literature search was conducted in the relevant databases, like ScienceDirect, PubMed, ResearchGate, and Google Scholar, to identify the studies. Conclusion: Tivozanib is an oral VEGFR-1, VEGFR-2, and VEGFR-3 tyrosine kinase inhibitor that is extremely selective and powerful. It has much less affinity for other receptor tyrosine kinases than multi-targeted TKIs now in clinical use. Because of its long half-life in circulation, it may be able to block VEGFRs more consistently. Doserelated controllable hypertension is its most commonly seen drug-related side event. Fatigue, hoarseness, and diarrhea, which are all common side effects, are not dose-related. Because of its target specificity, tivozanib can work well with other medications that have low side effects. Blocking both the VEGF and mTOR signaling pathways at the same time provides the benefit of synergistic antitumor efficacy while also preventing treatment resistance. Thus, overall we can say that the drug tivozanib is suitable for treatment in patients with renal cell carcinoma and can be investigated in multi-center clinical trials.

Each year, cancer claims the lives of around 10.0 million people worldwide. Food components have been shown to alter numerous intracellular signaling events that frequently go awry during carcinogenesis. Many studies suggest that dietary behaviors involving the consumption of antioxidant-rich foods, as well as caloric restriction, may play an important role in cancer prevention. Gene expression patterns, such as genetic polymorphisms, can influence the response to food components by altering their specific action on targets, as well as absorption, metabolism, and distribution, among other things. This review discusses two significant cancer prevention techniques: a vitamin-rich diet and caloric restriction. It also discusses the possible molecular interactions between the two dietary strategies and the first clues of a probable synergy that would come from combining caloric restriction with antioxidant use. Caloric restriction diets have positive effects on life expectancy and enable avoidance of age-related illnesses. As a result, this manuscript is based on the degenerative nature of cancer and intends to shed light on the biochemical features of not just calorie restriction but also vitamins. Both are thought to have an effect on oxidative stress, autophagy, and signaling pathways involved in energy metabolism and mitochondrial functions.

Background: Cancer cells restrain apoptotic and senescence pathways through intracellular heat shock protein 70 (Hsp 70). These cells aid stimulus-independent growth, and their higher metabolism rate requires Hsps. Hsps compensate abnormally increased substrate protein folding rate of cancer cells. Objective: Misfolding of substrate proteins especially signaling substrate proteins, may not function properly. Therefore, Hsp70 folds these substrate proteins into their native-fully functional states, and this mode of action helps cancer cell survival. Methods: Targeting Hsps is promising cancer therapy, and in this study, 6,8,9-trisubstituted purine derivatives were designed and synthesized to inhibit Hsp70 and drive cancer cells to apoptosis. Further, oncogenic stimuli through inhibitors can induce an irreversible senescent state and senescence is a barrier to transformation. Results: Hsp70 helps cancer cells to bypass the cellular senescence program, however, binding of N6-(4- isopropylaniline) analogue (7) depletes Hsp70 function as evidenced by aggregation assay and Hsp70 depletion induces senescence pathway. Conclusion: The purine-based inhibitor-compound 7 effectively inhibits MCF-7 cell line. Moreover, the therapeutic potential with regard to the senescence-associated secretory phenotype has complementary action. Dual action of the inhibitor not only drives the cells to apoptosis but also force the cells to be in the senescence state and provides promising results specially for luminal A type breast cancer therapy.

Background: Cancer is a major public health problem worldwide, and is the leading cause of death. The discovery and development of cancer therapeutic drugs have become the most urgent measure, which significantly benefited from the usage of small molecule compounds. The quinoline core possessed a vast number of biological activities that were found to be imperative. Objective: The aim is to design, synthesize and perform the biological evaluation of novel quinoline derivatives as potential anti-proliferative agents. Methods: Quinoline as a privileged scaffold was adopted to introduce diverse effective nitrogen heterocycles through different linkers. The synthesized compounds were spectroscopically characterized and evaluated for their anti-proliferative activity using the CCK8 assay. The mechanism of action was investigated by flow cytometry and the inhibitory activity against Pim-1 kinase was measured by mobility shift assay. Molecular docking analysis was performed to rationalize biochemical potency as well. Results: The majority of these quinolines displayed potent growth inhibitory effects, among which compounds 13e, 13f and 13h were the most effective ones, with GI50 values of 2.61/3.56, 4.73/4.88 and 4.68/2.98 μM, respectively. Structure-activity relationships indicated that both appropriate heterocycles at the C4 position of pyridine and suitable substituent at quinoline had a significant impact on improving activity. Compounds 13e and 24d exhibited moderate Pim-1 kinase inhibitory activity. Conclusion: In this study, three series of novel molecules bearing quinoline scaffold were designed, synthesized and evaluated for their in-vitro anti-proliferative activity. The most promising candidate, 13e, caused cell cycle arrest in a concentration-dependent manner and further induced apoptosis, which might represent a novel antiproliferative agent working through Pim-1 kinase inhibition to a certain extent.