**3. Conclusions**

A wide variety of kinase inhibitors have been recently published from marine-derived sources, including bacteria and cyanobacteria, fungi, animals, algae, soft corals and sponges. More than 100 kinase inhibitors of marine origin have been systematically documented for facile examination and comparison. An evaluation of the number of compounds reported during the period of this review, separated by the class of source organism, shows that there is a vast opportunity area for a kinase inhibitor research on the natural product chemistry of marine soft corals, especially (Figure 29). However, it should also be considered that from the overwhelming 58 kinase inhibitors reported from marine animals, soft corals, and sponges during this period, many are likely produced by symbiotic microorganisms. It is equally important to realize, however, that those symbionts may be di fficult or impossible to cultivate in laboratory conditions. It is thus of increasing importance that the development of selective kinase inhibitors from marine natural product drug discovery leads has utilized active fragment (pharmacophore) based medicinal chemistry to overcome supply limitations of natural product drug leads, and further optimize the drug-like properties of these molecules. In this way, each newly reported compound may provide marine-derived sca ffolds and bioactivity information for drug screening, and many have been found to have significant biological properties that could be used in the treatment of di fferent conditions such as cancers, inflammation, and neurodegenerative diseases, for example.

**Figure 29.** A breakdown by class of the reported producing organism for the marine derived natural product kinase inhibitors covered in this review period, from January, 2014 to February, 2019.

The noted structural di fferences and diversity of the marine natural products and their derivatives are important for chemical properties, conferring pharmacological e ffects, and of late-stage interest, intellectual property management. Some recent marine drug approvals include plitidepsin (aplidin), an ascidian natural product, and midostaurin, which is a synthetic derivative of the marine and terrestrial microbial molecule, staurosporine. There is also a pipeline of clinical trial candidates and preclinical development projects behind these drugs.

In recent years, new techniques including deep sea sampling, advanced methods in chemical synthesis, more e fficient target-based isolation [140], along with computational database mining strategies and high-throughput screenings have been widely helpful for drug candidate discovery and design. These all improve the e fficiency and success rate of the drug development process. Since kinases are directly implicated in so many aspects of disease development and progression in growth, successful targeting of these proteins has resulted in a number of novel drugs for cancer and neurodegenerative diseases and is expected to continue to do so. Nevertheless, while most of the approved kinase inhibitors are ATP binding site competitors, there is a dire need to overcome the toxicity associated with this liability. Hence, marine-derived natural product kinase inhibitors

could serve as lead compounds for development by medicinal chemistry. These diverse compounds greatly improve the chemical space covered during screening for new kinase inhibitors, with the goal of eventually providing new clinical candidates for unmet medical needs.

**Funding:** This research and the APC was funded by the National Key Research and Development Program of China (2018YFC0310900), the National Natural Science Foundation of China (81850410553, 41776168), the National 111 Project of China (D16013), the Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Development Fund, and the K.C. Wong Magna Fund in Ningbo University, the Natural Science Foundation of Ningbo City (2018A610410) and Foundation of Ningbo University for Grant (XYL18004).

**Conflicts of Interest:** The authors declare no conflict of interest.

## **List of Abbreviations**


