Design, synthesis, biological evaluation, and in silico studies of novel pyridopyridine derivatives as anticancer candidates targeting FMS kinase.

Design and synthesis of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives as novel rigid analogues of sorafenib are reported herein. The target compounds showed potent antiproliferative activities against a panel of NCI-60 cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising derivatives in terms of effectiveness and safety. Therefore, they were further examined to demonstrate their ability to induce apoptosis and alter cell cycle progression in hepatocellular carcinoma cells. The most potent compounds were tested against a panel of kinases that indicated their selectivity against FMS kinase. Compounds 8g and 8h showed the most potent activities against FMS kinase with IC50 values of 21.5 and 73.9 nM, respectively. The two compounds were also tested in NanoBRET assay to investigate their ability to inhibit FMS kinase in cells (IC50 = 563 nM (8g) and 1347 nM (8h) vs. IC50 = 1654 nM for sorafenib). Furthermore, compounds 8g and 8h possess potent inhibitory activities against macrophages when investigated in bone marrow-derived macrophages (BMDM) assay (IC50 = 56 nM and 167 nM, respectively, 164 nM for sorafenib). The safety and selectivity of these compounds were confirmed when tested against normal cell lines. Their safety profile was further confirmed using hERG assay. In silico studies were carried out to investigate their binding modes in the active site of FMS kinase, and to develop a QSAR model for these new motifs.

Targeting aldehyde dehydrogenase enzymes in combination with chemotherapy and immunotherapy: An approach to tackle resistance in cancer cells.

Modern cancer chemotherapy originated in the 1940s, and since then, many chemotherapeutic agents have been developed. However, most of these agents show limited response in patients due to innate and acquired resistance to therapy, which leads to the development of multi-drug resistance to different treatment modalities, leading to cancer recurrence and, eventually, patient death. One of the crucial players in inducing chemotherapy resistance is the aldehyde dehydrogenase (ALDH) enzyme. ALDH is overexpressed in chemotherapy-resistant cancer cells, which detoxifies the generated toxic aldehydes from chemotherapy, preventing the formation of reactive oxygen species and, thus, inhibiting the induction of oxidative stress and the stimulation of DNA damage and cell death. This review discusses the mechanisms of chemotherapy resistance in cancer cells promoted by ALDH. In addition, we provide detailed insight into the role of ALDH in cancer stemness, metastasis, metabolism, and cell death. Several studies investigated targeting ALDH in combination with other treatments as a potential therapeutic regimen to overcome resistance. We also highlight novel approaches in ALDH inhibition, including the potential synergistic employment of ALDH inhibitors in combination with chemotherapy or immunotherapy against different cancers, including head and neck, colorectal, breast, lung, and liver.

Design, synthesis, and biological evaluation of a new series of pyrazole derivatives: Discovery of potent and selective JNK3 kinase inhibitors.

The design, synthesis, and biological activities of a new series of pyrazole derivatives are reported. The target compounds 1a-1w were initially investigated against NCI-60 cancer cell lines. Compounds 1f, 1h, 1k, and 1v exerted the highest anti-proliferative activity over the studied panel of cancer cell lines. Compound 1f showed the most potent activity, and it is more potent than sorafenib in 29 cancer cell lines of different types and more potent than SP600125 against almost all the tested cancer cell lines. It also exerted sub-micromolar IC50 values (0.54-0.98 µM) against nine cell lines. Moreover, the 23 target compounds were tested against Hep3B and HepG2 hepatocellular carcinoma cell lines, of which compounds 1b, 1c, and 1h showed the strongest anti-proliferative activity. The most potent anticancer compounds (1b, 1c, 1f, and 1h) demonstrated a high selectivity towards cancer cells vis-à-vis normal cells. Compounds1f and 1h induced apoptosis and mild necrosis upon testing against RPMI-8226 leukemia cells. Kinase profiling of this series led to the discovery of two potent and selective JNK3 inhibitors, compounds 1c and 1f with an IC50 values of 99.0 and 97.4 nM, respectively. Both compounds showed a good inhibitory effect against JNK3 kinase in the whole-cell NanoBRET assay. This finding was further supported through molecular modeling studies with the JNK3 binding site. Moreover, compounds 1c and 1f demonstrated a very weak activity against CYP 2D6, CYP 3A4, and hERG ion channels.

Cancer immunotherapy resistance: The impact of microbiome-derived short-chain fatty acids and other emerging metabolites.

The landscape of cancer therapy has undergone dramatic changes over the past decade. Immune checkpoint inhibitors (ICIs) among various cancer immunotherapies have transformed the treatment paradigm for cancer therapy and improved the survival of patients. Nevertheless, oncologists are faced with key challenges that need to be overcome, such as the unpredictability of patient response to these therapies and the many immune-related adverse effects (irAEs). One major factor contributing to patient response to treatment is the composition of their gut microbiota. Many studies reported the role of gut microbiota in modulating immunotherapy. In particular, microbiota-derived metabolites, mainly short-chain fatty acids (SCFAs), have been the highlights of many studies exploring the association between the gut microbiome and patient sensitivity to cancer immunotherapy. This review discusses the role of gut microbiota-derived metabolites on patient response to ICIs and their potential use as predictive biomarkers and therapeutic targets to fine-tune, regulate, and enhance cancer immunotherapy.

Recent advances with alkaline phosphatase isoenzymes and their inhibitors.

Alkaline phosphatases are found in different living species and play crucial roles in various significant functions, such as hydrolyzing a variable spectrum of phosphate-containing physiological compounds, contributing to DNA synthesis, bone calcification, and attenuation of inflammation. They are homodimeric enzymes; each subunit contains one magnesium ion and two zinc ions crucial for the catalytic activity of the enzyme. Alkaline phosphatases exist in four distinct isoenzymes (placental, intestinal, germ cell, and tissue nonspecific alkaline phosphatases), which are expressed by four different genes; each one of them has distinguished functions. Any disturbance in the gene expression of alkaline phosphatase eventually induces serious disease conditions. Thus, the need to explore new lead inhibitors has increased recently. In this literature review, we aim to investigate the role of alkaline phosphatase in different diseases and physiological conditions and to study the structure-activity relationships of recently reported inhibitors. We focused on the lead compounds reported in the last 5 years (between 2015 and 2019).