Abstract
Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia, and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, SIX1, and vacuolar ATPases. We hypothesized that additional, yet undiscovered molecular targets might be associated with Manzamine A’s (MZA) reported pharmacological properties. We report here, for the first time, that MZA selectively inhibited a 90 kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases, while in vitro RSK kinase assays demonstrated a 10-fold selectivity in the potency of MZA against RSK1 versus RSK2. The effect of MZA on inhibiting cellular RSK1 and RSK2 protein expression was validated in SiHa and CaSki human cervical carcinoma cell lines. MZA’s differential binding and selectivity toward the two isoforms was also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2–MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes, including growth, survival, and proliferation. Consequently, our findings have led us to hypothesize that MZA and the currently known manzamine-type alkaloids isolated from several sponge genera may have novel pharmacological properties with unique molecular targets, and MZA provides a new tool for chemical-biology studies involving RSK1.
Highlights
Marine biological and chemical diversity continue to demonstrate significant potential to contribute novel pharmacology for multiple therapeutic categories [1]
As previously reported, BI-D1870, which which we used as a positive control, potently inhibited Ribosomal S6 Kinase 1 (RSK1) and Ribosomal S6 Kinase 2 (RSK2)
In support of our in vitro kinase assays and docking experiments, we further examined the biological effect of Manzamine A (MZA) on RSK1 and RSK2 protein expression levels, further examined the biological effect of MZA on RSK1 and RSK2 protein expression levusing SiHa and CaSki human cervical carcinoma cancer cell lines
Summary
Marine biological and chemical diversity continue to demonstrate significant potential to contribute novel pharmacology for multiple therapeutic categories [1]. The current marine pharmaceutical clinical pipeline consists mainly of compounds developed for cancer chemotherapy [2], several products have beento shown for cancer chemotherapy [2], several marinemarine naturalnatural products have been shown targetto a target a range of protein kinases as well [3]. Loss of RSK2 function causes a rare form of mental retardation [20]. We report that screening against a panel of protein kinases revealed MZA inhibited the RSK1 and RSK2 with a high potency toward RSK1. Computational experiments predicted that MZA binds to the ATPbinding pocket of NTKD RSK1, while putative binding affinities of MZA and ATP to the ATP-binding sites of a protein kinase panel offer comparative results pertaining to MZA’s target selectivity
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