Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment

Abstract

Protein Kinases (PKs) are a heterogeneous family of enzymes that modulate several biological pathways, including cell division, cytoskeletal rearrangement, differentiation and apoptosis. In particular, due to their crucial role during human tumorigenesis and cancer progression, PKs are ideal targets for the design and development of effective and low toxic chemotherapeutics and represent the second group of drug targets after G-protein-coupled receptors. Nowadays, several compounds have been claimed to be PKs inhibitors, and some of them, such as imatinib, erlotinib and gefitinib, have already been approved for clinical use, whereas more than 30 others are in various phases of clinical trials. Among them, some natural or synthetic carbazole-based molecules represent promising PKs inhibitors due to their capability to interfere with PK activity by different mechanisms of action including the ability to act as DNA intercalating agents, interfere with the activity of enzymes involved in DNA duplication, such as topoisomerases and telomerases, and inhibit other proteins such as cyclindependent kinases or antagonize estrogen receptors. Thus, carbazoles can be considered a promising this class of compounds to be adopted in targeted therapy of different types of cancer.

Evaluation of small molecule kinase inhibitors as novel antimicrobial and antibiofilm agents

“…Two fragments, F1 ( 14) and F2 (15), were identified in this screen by increasing the Tm of both WalK and NblS (Figure 2). F1 is an arylated 2-aminothiazole and F2 is a substituted carbazole, two structures that have been identified in other screens as kinase inhibitors in both mammalian and bacterial systems (Bashir et al, 2015;Ceramella et al, 2020;Das et al, 2006;Helal et al, 2004;Lindenblatt et al, 2020;Liu et al, 2015;Misra et al, 2004). Autophosphorylation assays with radiolabeled γ-32 P-ATP substrate revealed that both F1 and F2 display weak inhibition of autophosphorylation in WalK, as expected for fragment compounds (Velikova et al, 2016).…”

PKG II secreted via the classical endoplasmic reticulum--Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect

“…Protein Kinases are a heterogeneous family of enzymes modulating several biological pathways, including cell survival, differentiation and apoptosis [1]. As a serine/threonine-protein kinase, Protein kinase G type II (PKG II) was first detected as a membrane-bound receptor of cyclic guanosine monophosphate (cGMP) in the intestinal epithelium [2] and later found to bind to the cellular membrane via a myristoyl moiety attached to the Nterminus of the amino acid (aa) chain [3].…”

Diarylureas as Antitumor Agents

“…These compounds circumvent kinases in an inactive state, the so-called DFGout, and occupy a hydrophobic pocket next to the ATP-binding site. The diarylurea fragment is able to link the hinge-binding moiety with the portion that occupies the hydrophobic pocket that is in the inactive conformation of kinases [17] (Figure 2). Diarylureas represent the skeleton of the main systemic therapies for several cancers, as advanced, metastatic hepatocellular carcinoma (HCC) [18], advanced renal cell carcinoma (RCC) [19], gastrointestinal stromal tumors (GISTs) [20], metastatic colorectal cancer (mCRC) [21].…”