Current Topics in Medicinal Chemistry - Volume 20, Issue 12, 2020

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

Natural Products (NP), specifically from medicinal plants or herbs, have been extensively utilized to analyze the fundamental mechanisms of ultimate natural sciences as well as therapeutics. Isolation of secondary metabolites from these sources and their respective biological properties, along with their lower toxicities and cost-effectiveness, make them a significant research focus for drug discovery. In recent times, there has been a considerable focus on isolating new chemical entities from natural flora to meet the immense demand for kinase modulators, and also to overcome major unmet medical challenges in relation to signal transduction pathways. The signal transduction systems are amongst the foremost pathways involved in the maintenance of life and protein kinases play an imperative part in these signaling pathways. It is important to find a kinase inhibitor, as it can be used not only to study cell biology but can also be used as a drug candidate for cancer and metabolic disorders. A number of plant extracts and their isolated secondary metabolites such as flavonoids, phenolics, terpenoids, and alkaloids have exhibited activities against various kinases. In the current review, we have presented a brief overview of some important classes of plant secondary metabolites as kinase modulators. Moreover, a number of phytocompounds with kinase inhibition potential, isolated from different plant species, are also discussed.

Background: The EGFR is overexpressed in numerous cancers. So, it becomes one of the most favorable drug targets. Single-acting EGFR inhibitors on prolong use induce resistance and side effects. Inhibition of EGFR and/or its interacting proteins by dual/combined/multitargeted therapies can deliver more efficacious drugs with less or no resistance. Objective: The review delves deeper to cover the aspects of EGFR mediated endocytosis, leading to its trafficking, internalization, and crosstalk(s) with HDACs. Methods and Results: This review is put forth to congregate relevant literature evidenced on EGFR, its impact on cancer prognosis, inhibitors, and its trafficking regulation by acetylation along with the current strategies involved in targeting these proteins (EGFR and HDACs) successfully by involving dual/hybrid/combination chemotherapy. Conclusion: The current information on cross-talk of EGFR and HDACs would likely assist researchers in designing and developing dual or multitargeted inhibitors through combining the required pharmacophores.

Bryostatins are complex macrolactones isolated from marine organisms Bryozoan Bugula neritina. They are potent modulators of protein kinase C isozymes (PKCα: ki = 1.3-188 nM), and are one of the most extensively investigated marine natural products in clinical trials. Although ~21 natural bryostatins have been isolated, however only bryostatin-1 (1) has received much interest among medicinal chemists and clinicians. The structure-activity relationship of bryostatins has been well established, with the identification of key pharmacophoric features important for PKC modulation. The low natural abundance and the long synthetic route have prompted medicinal chemists to come-up with simplified analogs. Bryostatin skeleton comprises three pyran rings connected to each other to form a macrocyclic lactone. The simplest analog 27 contains only one pyran, which is also able to modulate the PKCα activity; however, the cyclic framework appears to be essential for the desired level of potency. Another simplified analog 17 (“picolog”) exhibited potent and in-vivo efficacy against lymphoma. Bryostatin-1 (1) has shown an acceptable intravenous pharmacokinetic profile in mice and displayed promising in-vivo efficacy in mice models of various cancers and Alzheimer's disease. Bryostatin-1 was investigated in numerous Phase I/II oncology clinical trials; it has shown minimal effect as a single agent, however, provided encouraging results in combination with other chemotherapy agents. FDA has granted orphan drug status to bryostatin-1 in combination with paclitaxel for esophageal cancer. Bryostatin-1 has also received orphan drug status for fragile X syndrome. Bryostatin-1 was also investigated in clinical studies for Alzheimer's disease and HIV infection. In a nutshell, the natural as well as synthetic bryostatins have generated a strong hope to emerge as treatment for cancer along with many other diseases.