**1. Introduction**

Oceans and seas occupy almost 70% of the Earth's surface, and are estimated to host about 80% of all living species [1]. The rich biodiversity of the marine environment has been shown to yield equally rich chemical diversity of marine natural products isolated from the different organisms that have been studied since the 1940s [2]. In the same time period, roughly two-thirds of small molecules drugs with FDA or equivalent regulatory agency approvals have been granted for natural products or derivatives thereof [3]. This has certainly included many exceptionally impactful antibiotic or antiparasitic drugs and oncology therapeutics, among others [4–7]. Indeed, the published structures of natural products appear to correlate well with the chemical space occupied by approved drugs, and the natural product drug discovery continues to yield new and interesting compounds [2,8,9]. According to the MarinLit database (http://pubs.rsc.org/marinlit), more than 28,000 marine natural products have been reported after being isolated from a variety of marine sources; such as algae, ascidians, bryozoa, corals, microorganisms, sea hares, sea squirts, sponges, etc. [10]. The known and yet-to-be discovered marine natural product compounds represent a vast natural resource library. In the golden age of natural product research, many marine-derived scaffolds have been applied to clinical drug discovery and development due to new ideas and breakthroughs in screening technologies: (a) The mesophotic zone is increasingly recognized as being valuable for the discovery of new drug structures and unique activities [11]; (b) Computational methodologies play an essential role in the exploration of the biological activity and molecular structural networking of marine natural products [12]; (c) Databases of marine natural products (e.g. MarinLit: http://pubs.rsc.org/marinlit/ and Dictionary of Marine Natural Products: http://dmnp.chemnetbase.com/) are available to facilitate dereplication and discovery efforts and improve marine natural products research; (d) Chemical synthesis of complex molecules has become increasingly feasible at even gram-scale quantities that allow for the further biological interrogation and drug development of natural products previously isolated in low yields [13].

Most of the kinase inhibitor drugs approved thus far are adenosine triphosphate (ATP) competitive inhibitors that have various practical off-target liabilities. Four major classes of kinases exist in mammalian signaling pathways, and these can be classified broadly by substrate specificity: Serine/threonine kinases, tyrosine kinases, dual kinases (both Ser/Thr and Tyr), and lipid kinases [14]. Protein kinases share a common mechanism that is demonstrated in Figure 1, in which the protein function is activated or inactivated by the transfer of a phosphate group from ATP to the free hydroxy of a serine, threonine or tyrosine on the targeted protein, whereas protein phosphatases remove a phosphate group from phosphorylated amino acids and thereby effectively reverse the effect [15–18]. There are 38 FDA-approved small molecule kinase inhibitors available for the treatment of different diseases, such as cancers, immunological, inflammatory, degenerative, metabolic, cardiovascular and infectious diseases [19,20], and many more candidates still in clinical development. Some new biological therapeutics, in the way of monoclonal antibodies, have been discovered or engineered to successfully target some kinases [21,22]. A major challenge in the development of new kinase inhibitors is to overcome the toxicity or non-specificity of the existing drugs that act as ATP binding site competitors. Since small-molecule natural products are produced by and interact with proteins in their natural settings, some are known to function as signaling molecules among many forms of life and have been creatively repurposed for human health applications. Accordingly, some marine natural products have served as drug lead compounds, and these provide an abundant resource for the discovery of next-generation kinase inhibitors that target allosteric regions away from the ATP binding sites [23–26] or by stabilizing inactive conformations to prevent the function of certain kinases [27–30]. This is particularly relevant for the treatment of cancers and bacterial infections.

This review provides insight into the kinase inhibitors isolated from marine sources (bacteria and cyanobacteria, fungi, animals, algae, soft corals and sponges) that have been reported in the last five years since 2014 and highlight the associated biological activities and potential clinical applications. Examples of successful applications of marine natural products lead compound discovery and use of new drug screening technologies that have enabled rapid expansion in the field are accordingly provided.

**Figure 1.** The catalytic cycle for protein phosphorylation by a protein kinase. Red circles represent phosphate groups. Adapted from content in Ref [16].
