The search for pharmaceutically active compounds from natural sources is well established, with approximately 70% of small molecule drugs produced between 1981 and 2006 possessing an important link to a natural product source [1]. The pharmaceutical value of natural products is even more exemplified in the critical area of anticancer drugs, whereupon of the 155 small-molecules produced from the 1940s, 73% are other than “synthetic”, with 47% being natural products or natural product derived [1]. With oceans covering 70% of the surface of the earth, coupled with the large and varied biodiversity of the marine environment, the oceans remain a largely unexplored, but extremely promising source of new drug candidates. Approximately half of the novel marine natural products reported in the literature are biologically active [2]. This occurrence can be contributed to the reliance of sessile, soft-bodied marine invertebrates on chemical defense for survival, as many lack the physical defense mechanisms of movement and camouflage. As these chemicals are released into the water and are rapidly diluted, these secondary metabolites produced are often extremely potent [3].

The protein kinase family encompasses all enzymes in the human body that catalyse the chemical transfer of a phosphate group from a high energy molecule such as adenine triphosphate (ATP) to a specific substrate. The human genome encodes for approximately 518 different protein kinases, which are divided into different kinase families on the basis of their selectivity for substrates [4]. The covalent attachment of a phosphate group to a substrate requires a free hydroxyl moiety, and there are three amino acids that can provide this; serine, threonine and tyrosine. Therefore, serine/threonine kinases will recognise and attach a phosphate group to a serine or threonine amino acid, while the tyrosine-specific protein kinase family will phosphorylate a protein at a tyrosine moiety.

Kinases play a large, varied and vital role in cell regulation and particularly in signal transmission pathways, controlling cell differentiation, proliferation, metabolism, DNA damage repair, cell motility, response to external stimuli and apoptosis [5]. Deregulation of kinases has been found to be a primary cause in an increasing list of diseases, including oncological diseases, central nervous system disorders, autoimmune diseases, metabolic diseases and osteoporosis, suggesting that the number of kinases with the potential to be new pharmaceutical targets is significantly large [6]. The current focus on kinases is in the development of drugs with lower side effects than previous cancer treatments which traditionally focused on DNA replication and chromosome regulation and thus also affected many healthy cells. As various kinases have been reported to be misregulated in cancerous cells, anticancer treatments involving kinases can be specifically targeted to cancer cells [4]. The development of kinase inhibitors has been predicted to be a major driver of pharmaceutical growth with more than 130 kinase inhibitors reported to be in either Phase I or Phase II clinical trials, the majority of these being tested for their potential as cancer treatments [7]. Kinase inhibitors that successfully proceed onto the pharmaceutical market will join Imitinib (Gleevec, Novartis), a tyrosine kinase inhibitor that has dramatically improved the prognosis for sufferers of chronic myeloid leukemia after being the first small-molecule kinase inhibitor to be approved for human use [6]. Herein, we review the recent highlights and developments of over 70 kinase inhibitors that have been isolated from marine sponges.

Kinase inhibitors and activators from natural sources were covered in 2011 by Marston in a review that included a small number of marine natural products [8]. In 2007, Nakao and Fusetani published a review on enzyme inhibitors isolated from marine organisms which included some protein kinase inhibitors from marine sponges [9]. In 2009, Deslandes et al. reviewed the synthesis and kinase inhibitory activities of the marine natural products granulatimide and isogranulatimide [10]. In 2009, Nguyen et al. published the synthesis and evaluation of the kinase inhibitory activity of the sponge derived compound hymenialdisine and its analogues [11]. In 1998, Carter and Kane reviewed the therapeutic potential of natural compounds that regulate the activity of protein kinase C [12]. To the best of the authors’ knowledge, this is the first comprehensive review that is focussed solely on the kinase inhibitory activities of marine sponge metabolites.

The family of kinases known as protein kinase C (PKC) are serine/threonine kinases that encompass eleven isozymes and through the action of phosphorylating various intracellular proteins, mediate many physiological events such as induction of cell differentiation, regulation of apoptosis and inhibition of tumor invasion [13]. Protein kinase C is composed of two distinct regions; a carboxyl-terminal catalytic site containing an adenine triphosphate (ATP) binding site and a regulatory domain at the amino terminal that possesses a phorbol-binding domain that is unique to the PKC family [14]. The catalytic site on PKC is structurally shared amongst many different classes of kinases, and as such PKC inhibitors that block this site can also inhibit the action of other functionally diverse kinases [14]. Natural activators of PKC include diacylglycerols, phosphatidyl serine, inositol triphosphate and calcium ions. The vital role that PKCs play in signal transduction pathways has marked them as potential targets for pharmaceutical inhibition of diseases such as cancer, cardiovascular disease, renal disease, immunosuppression and autoimmune disease [15].

The efficacy of the natural product staurosporine as a PKC inhibitor has been known since last century when the alkaloid was isolated from the bacteria Streptomyces staurosporeus and shown more recently to have an IC₅₀ value of 2.7 nM against PKC [16]. In recent years, a variety of marine organisms have also provided important PKC modulators such as 11-hydroxystaurosporine from the marine tunicate Eudistoma sp. [17] and bryostatin-1, from the marine bryozoan Bugula neritina [14,18]. Marine sponges have also proven to be a particularly rich source of PKC inhibitors.

In 1994, the sponge Xestospongia sp. collected in waters off the Papua New Guinea coast, furnished xestocyclamine A (1, Figure 1) bearing a novel skeleton and found to inhibit PKC with an IC₅₀ value of 4 μg/mL [19]. Xestocyclamine A and its pure enantiomer (−)-xestocyclamine A are considered critical PKC inhibitors for use in the development of anticancer drugs and there are many research groups focused on synthesising the stereochemically complex marine alkaloids [20,21]. (Z)-Axinohydantoin (2, Figure 1) and debromo-Z-axinohydantoin (3, Figure 1) are two PKC inhibitors with respective IC₅₀ values of 9.0 and 22.0 μM that were isolated from the marine sponge Stylotella aurantium [22]. These novel compounds were isolated during a scale-up collection of the PKC inhibitors, hymenialdisine (4, IC₅₀ 0.8 μM, Figure 1) and debromohymenialdisine (5, IC₅₀ 1.3 μM, Figure 1) from the same sponge species [22]. Hymenialdisine is found to inhibit a range of kinases (see Section 4.1).

Five novel sesquiterpene derivatives, frondosins A–E (6–10, Figure 1), were isolated from the marine sponge Dysidea frondosa and shown to have inhibitory activity against PKC with reported IC₅₀ values of 1.8, 4.8, 20.9, 26.0 and 30.6 μM respectively [23]. Frondosins A–E were also reported to be inhibitors of interleukin-8 in the low micromolar range [23] and more recently (−)-frondosins A (6) and D (9) have shown comparable activity against the HIV virus [24]. Various synthetic routes to frondosins A–C have been reported [25–27].

BRS1 (11, Figure 1), a polyunsaturated lipid isolated from an unidentified Australian sponge of class Calcarea was reported to be a novel inhibitor of PKC [28]. BRS1 exerts it activity by binding to the phorbol ester binding site and accounts for 0.02% of the wet weight of the sponge from which it was collected. The IC₅₀ of BRS1 for inhibiting the binding of the phorbol ester was 9 μM, whereas 98 μM represented a 50% effective concentration for inhibiting the enzymatic activity of PKC [28].

An Okinawan marine sponge belonging to the family Spongiidae, has furnished a family of novel sesquiterpenoid quinones, including the nakijiquinones A–D (12–15, Figure 1), with reported IC₅₀ values against PKC of 270, 200, 23 and 220 μM respectively [29,30]. A subsequent paper described the isolation of the nakijiquinones G–I (16–18) from the same sponge, which showed modest cytotoxicity in the range of 2.4 to >10 μg/mL against a range of cancer cell lines (e.g., P388 murine leukemia, L1210 murine leukemia and KB human epidermal carcinoma cells), as well as inhibitory activity against HER2 kinase [31]. The remarkable inhibitory activity of nakijiquinones A–D against a variety of kinases including epidermal growth factor receptor (EGFR), c-erbB-2 kinase and tyrosine kinase VEGFR2 has been reviewed and their biological activity and structure-activity relationships are well documented [15,32]. The synthesis of the nakijiquinones has been reported [33,34], with particular emphasis on the potential of nakijiquinone and its analogues in the prevention of angiogenesis as the nakijiquinone family is the only naturally occurring inhibitor of the Her-2/Neu receptor tyrosine kinase. Extensively implicated in tumor proliferation, the Her-2/Neu receptor tyrosine kinase is over-expressed in approximately 30% of primary breast, ovary and gastric cancers and when amplified has been linked to increases in the aggressiveness of the cancer and reduced patient survival [35].

The cytotoxic sesterpenes spongianolides A–E (19–23, Figure 1), isolated from a marine sponge belonging to the genus Spongia, were found to have inhibitory activity against PKC with IC₅₀ values ranging between 20–30 μM [36]. The cheilanthane cyclic terpenoid contained within the structure has since been synthesized via a biomimetic approach [37] (see also Section 7).

Another potent marine sponge derived PKC inhibitor is lasonolide A (24, Figure 1). Isolated from the Caribbean sponge Forcepia sp., lasonolide A was found to inhibit the phorbol ester-stimulated adherence of EL-4.IL-2 mouse thymoma cells within 30 min with an IC₅₀ value of 27 nM, highlighting the potential of this compound for development as a potent PKC inhibitor [38–40].

Another inhibitor of PKC enzyme is a new azetidine compound penazetidine A (25, Figure 1) isolated from the Indo-Pacific marine sponge Penares sollasi [41]. This sponge species attracted attention after its crude extract in initial screenings exhibited inhibitory activity (IC₅₀ 0.3 μg/mL) against serine kinase PKC-βI, but it was not active against protein tyrosine kinase (PTK). Penazetidine A displayed strong activity against PKC (IC₅₀ l μM), and also showed significant cytotoxicity against human and murine cancer cell lines (A549, HT-29, B16/F10 and P388) [41]. A mixture of two diastereomeric spirosesquiterpene aldehydes, corallidictyals A and B, were isolated from the marine sponge Aka (=Siphonodictyon) coralliphaga, which was collected at Little San Salvador Island (26, 27, Figure 1) [42]. This mixture was found to show good selectivity for the inhibition of PKC (IC₅₀ 28 μM) compared to the other serine kinase enzyme PKA (IC₅₀ 300 μM). In particular, the diastereomeric mixture was selective for inhibition of the α-PKC isoform giving a lower IC₅₀ value compared to the other isoforms of the enzyme.

Cyclin-Dependent kinases (CDKs) are a group of serine/threonine kinases that encompass approximately 25 different cyclin families, all of which are critical in the regulation of the cell cycle [4]. The distinguishing feature of the CDKs from other kinase families is the enzymatic activation requirement of the binding of the cyclin regulatory subunit [43]. The movement of the cell through the cell cycle phases is determined by the fluctuating concentrations of different activated CDK/cyclin complexes whose cellular mechanism involves the phosphorylation of many distinct proteins at serine or threonine residues in specific sequences. While CDKs are also involved in apoptosis and transcription, their pivotal role in differentiation, transformation, proliferation and metastasis has recently seen CDKs become a major target for cancer therapies, especially now that it is recognized that hyperactive CDKs (overexpression) or hypoactive CDKs (mutation, deletion) are a leading cause of uncontrolled tumor proliferation in humans [4]. Several natural and synthetic compounds that inhibit CDKs in the sub-micromolar range have been isolated and are at various stages of clinical trials, the most advanced being flavopiridol, a semi-synthetically produced analogue of an alkaloid from the Indian tree Dyoxylum binectariferum, currently in Phase II clinical trials for soft tissue sarcomas [44]. These small molecule inhibitors arrest tumor proliferation and many are also capable of inducing apoptosis in proliferating cells [45].

Tyrosine protein kinase (TPK) are enzymes that catalyse the phosphorylation of tyrosine residues and can be divided into two main categories; cellular and receptor TPKs, and non-receptor TPKs. Studies into this particular class of kinase have identified them as key players in both intracellular and extracellular communication [64]. TPKs are associated with proliferative diseases such as cancer, leukemia, psoriasis and restonosis due to their role in regulating key cell functions like proliferation, differentiation, and antiapoptotic signaling [64] and it has been reported that 70% of the known oncogenes and proto-oncogenes found in cancer are associated with TPKs [65].

The deep-sea sponge Ircinia sp. collected off the New Caledonian coast at a depth of 425–500 m yielded three TPK inhibitors, the penta-, hexa- and hepta-prenylhydroquinone 4-sulfates (38–40, Figure 3). IC₅₀ values for each compound against TPK were recorded as 8, 4 and 8 μg/mL respectively [66]. Penta-prenylhydroquinone sulfate (38, Figure 3) has also proven to be a potential antiviral and cytotoxic agent achieving 65% inhibition of the HIV-1 integrase enzyme at 1 μg/mL and having inhibited neuropeptide Y (NPY) receptor with an IC₅₀ value of 50.8 μg/mL. This compound also displayed cytotoxicity against the epidermal KB carcinoma cell line [66].

The epidermal growth factor receptor (EGFR) is a member of the type 1 growth factor receptor gene family, which also includes erbB-1, erbB-2, erbB-3 and erbB-4 [74]. This tyrosine kinase family has been heavily implicated in the mechanisms of various cancers as mutations leading to EGFR being over-expressed have often been found in cancer cases, in particular breast cancer [15]. As part of an extensive effort to identify small molecule inhibitors of this drug target, two novel bromopyrrole alkaloids were isolated from an Okinawan marine sponge Hymeniacidon sp. and named tauroacidins A and B (48, 49, Figure 4) [75]. These two compounds showed inhibitory activity against both EGFR and c-erbB-2 kinase with an IC₅₀ value of 20 μg/mL for each respective kinase [75]. The tauroacidins A and B may be biogenetically related to other bromopyrrole alkaloids from marine sponges through the taurine residue attached to the aminoimidazole ring [75]. Okinawan marine sponges have proven to be a particularly rich source of kinase inhibitors with a bromotyrosine alkaloid, ma’edamine A (50, Figure 4), also being isolated from the Okinawan marine sponge Suberea sp. and showing inhibitory activity against c-erbB-2 kinase (IC₅₀ 6.7 μg/mL) [76]. Ma’edamine A contains a unique 2(1H)pyrazinone moiety located between the two bromotyrosine units, and also displays cytotoxicity against murine leukemia L1210 cells (IC₅₀ 4.3 μg/mL) and epidermal KB carcinoma cells (IC₅₀ 5.2 μg/mL) [76].

Spongiacidins A and B (51, 52, Figure 4) are inhibitors of c-erbB-2 kinase isolated from the Okinawan marine sponge Hymenacidon sp. [77]. These two compounds are also bromopyrrole alkaloids of the pyrrolo[2,3-c]azepine type. The respective IC₅₀ values for spongiacidins A and B against c-erbB-2 kinase are 8.5 and 6.0 μg/mL [77]. It was later identified that spongiacidin A is actually the (E) isomer at the exocyclic C10-C11 double bond of 3-bromohymenialdisine, a metabolite of hymenialdisine discussed earlier [78].

Isolated from the marine sponge species Verongia aerophoba, (+)-aeroplysinin-1 (53, Figure 4) was found to completely inhibit EGFR at a concentration of 0.5 μM [79]. Due to this inhibitory ability, (+)-aeroplysinin-1 was found to have a strong antitumor effect on EGFR tumor cell lines, in particular blocking the proliferation of EGFR dependent human breast cancer cell lines MCF-7 and ZR-75-1 [79]. Importantly, (+)-aeroplysinin-1 displays some selectivity for cancerous cells as the application of (+)-aeroplysinin-1 at a concentration of 0.25–0.5 μM resulted in total tumor cell death, but did not have any cytotoxic effect on normal human fibroblasts at concentrations ten times higher [79]. A recent study has identified (+)-aeroplysinin-1 as an important inhibitor of several key steps of angiogenesis, the process by which tumors become mutagenic and thus a vital target for pharmaceutical intervention in cancerous diseases [80]. In detail, (+)-aeroplysinin-1 has been shown to inhibit capillary-like tube formation, induce apoptosis, promote anti-proteolysis in endothelial cells and also arrest the development of new vascular structures [80]. As angiogenesis is a major factor in fatal cancers and (+)-aeroplysinin-1 displays in vivo efficacy as an inhibitor of this process, it remains an extremely promising drug candidate.

Three novel compounds identified as 3,9-dimethyldibenzo[b,d]furan-1,7-diol (54), 3-(hydroxymethyl)-9-methyldibenzo[b,d]furan-1,7-diol (55), 1,7-dihydroxy-9-methyldibenzo[b,d] furan-3-carboxylic acid (56) and one known compound, butyrolactone derivative (57), were isolated from marine sponge Acanthella cavernosa from Fiji and all compounds displayed moderate inhibitory properties against EGFR [81]. In recent studies, bioassay-guided fractionation of the marine sponge Spongionella sp., yielded the novel bioactive diterpenes, 3′-norspongiolactone (58, Figure 4) and gracilins J–L (59–61), along with three known gracilins and the known diterpenoid tetrahydroaplysulphurin-1 [82]. All eight compounds isolated from the sponge Spongionella sp. exhibited cytotoxicity against the K562 human chronic myelogenous leukemia cell lines with IC₅₀ values in the range of 0.6 to 15 μM, however they also showed similar levels of cytotoxicity towards human peripheral blood mononuclear cells (PBMC) [82]. All compounds displayed inhibitory activity towards EGFR tyrosine kinase with the novel diterpenes 58–61 exhibiting 25%, 19%, 75% and 57% inhibition respectively at 100 μM [82].

Mitogen- and stress-activated kinase (MSK1) and mitogen-activated protein kinase (MAPK) are two stress-associated serine/threonine specific protein kinases involved in cellular signaling, regulating various processes such as cell division and proliferation, apoptosis and gene expression [83]. There are three major subclasses of this kinase family, including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPKs) and p38 MAPKs [83]. It has been acknowledged that selective inhibitors of these kinases are likely to affect cellular events with high specificity and are therefore molecules of significant interest in the search for anticancer pharmaceuticals [15].

In the first description of cheilanthane sesterterpenoids from a marine sponge, three novel (62–64) and one known cheilanthane sesterterpenoids (65, Figure 5) were isolated from the marine sponge Ircinia sp., with 62, 63 and 65 obtained as inseparable 1:1 mixtures of their C-25 epimers. Intriguingly, all four compounds were reported to exhibit identical inhibitory activity against MSK1 (IC₅₀ 4 μM for each compound) and mitogen activated protein kinase activated protein kinase (MAPKAPK-2, IC₅₀ 90 μM for each compound) [84]. Extracts from two sponge species, the purple bleeding sponge Iotrochota birotulata and the West Indian bath sponge Spongia barbara were found to inhibit the MAPK/ERK cascade, a pathway that links the binding of growth factors on cell surface receptors to intracellular responses [85]. Encompassing many protein kinases, activation of this cascade leads to cell division and is thus a potential anticancer drug target [86]. The two extracts significantly inhibited the MAPK/ERK pathway to 51% and 44% of control levels respectively without affecting the survival of the cell [85].

A serine/threonine protein kinase, the main function of glycogen synthase kinase-3 (GSK-3) is the mediation of glycogen synthase but it is also involved in several key cellular events such as the response to damaged DNA and the phosphorylation of the microtubule associated mammalian protein tau. Overactivity of this phosphorylation has been identified as one of the first events in the onset of neurodegenerative diseases such as Alzheimer’s disease [96]. Over the last two decades, interest in GSK-3 has exponentially increased as its potential as a drug target in many non-curable diseases such as type-2 diabetes, stroke, Alzheimer’s disease, and bipolar disorder is recognized [96]. Current small molecule inhibitors of GSK-3 include pyridyloxadiazoles, thiadiazolidindiones, pyrazolopyrimidines and maleimides [96], but marine sponges are also proving to be a reliable source of secondary metabolites showing inhibitory activity against this drug target.

Manzamine A (71, Figure 6), a complex alkaloid isolated from an Okinawan sponge of the genus Haliclona, is one such compound showing specific non-competitive inhibition of ATP binding in GSK-3β with an IC₅₀ value of 10.2 μM [96]. Manzamine A also inhibits CDK-5 with an IC₅₀ value of 1.5 μM, and as this kinase coupled with GSK-3 represents the two main players in the hyperphosphorylation mechanism in Alzheimer’s disease, manzamine A is a useful drug lead for the future treatment of this disease [96]. This conclusion is supported by the fact that manzamine A has proved capable of entering cells and interfering with the tau protein as well as causing arrest in the hyperphosphorylation in human neuroblastoma cell lines [96]. Structure-activity relationships between manzamine A and the GSK-3 pharmacophore have been carried out and a variety of manzamine A analogues have also been synthesized indicating that the entire manzamine molecule is required for GSK-3 inhibitory activity [96]. Manzamine A and its synthesized derivative (−)-8-hydroxymanzamine A, have also been identified as promising new antimalarial agents producing in vivo inhibition of the growth of the malaria parasite Plasmodium berghei in rodents [97]. As the malaria parasite rapidly achieves resistance to currently administered antimalaria drugs, patents for the use of manzamine A in human antimalarial drugs have been submitted [98].

The carteriosulfonic acids A–C (72–74, Figure 6), novel compounds containing a 4,6,7,9-tetrahydroxylated decanoic acid subunit, were recently identified during a screen to identify modulators of Wnt signaling, which plays a key role in cell proliferation [99]. Phosphorylation of β-catenin by GSK-3β is involved in the negative regulation of Wnt signaling and thus it was proposed that inhibitors of GSK-3β may be associated with Wnt signaling activation. Accordingly, the compounds (72–74) were isolated from an extract of the marine sponge Carteriospongia sp., which was a Wnt signaling activator and were found to be low micromolar inhibitors of GSK-3β. Although further biological studies were foreshadowed in the above article, they had not yet appeared at the time of writing this review [99].

Liphagal (75, Figure 7), a meroterpenoid isolated from the marine sponge Aka coralliphaga collected in Dominica, was found to exhibit inhibitory activity against PI3K (phosphoinositide-3-kinase) with an IC₅₀ value of 100 nM, with 10 folder higher potency against PI3Kα than towards PI3Kγ [100,101]. This compound also exhibited cytotoxicity against human colon (IC₅₀ 0.58 μM) and human breast (1.58 μM) tumor cell lines [100]. This sponge species is also known to produce the PKC inhibitors corallidictyals A and B (26 and 27) (see Section 3). Two bisabolene type sesquiterpenoids, (+)-curcuphenol (76, Figure 7) and (+)-curcudiol (77, Figure 7) were identified as bioactive compounds from the sponge Axynissa sp. from Indonesia. Curcuphenol showed Src protein kinase inhibition with an IC₅₀ value of 7.8 μg/mL, while curcudiol inhibited focal adhesion kinase (FAK) with an IC₅₀ value of 9.2 μg/mL [102]. Protein kinase A inhibitory activities of up to 100% (at 100 μg/mL) along with haemolytic and brine shrimp activities were also observed in a range of extracts isolated from three deep-water sponges collected from North Western Australia [103]. A novel compound, homogentisic acid (78) was isolated from the sponge Pseudoceratina collected in Vanuatu [104]. The authors previously isolated xestoquinone from a Xestospongia sp. collected from the same place and in their research for new antimalarial drugs found that this compound was an inhibitor of Pfnek-1, which is a NIMA-related protein kinase of Plasmodium falciparum. Therefore homogentisic acid was also screened against Pfnek-1 and found to display an IC₅₀ value of 1.8 μM against this target [104] Hymenialdisine (4) has also showed Polo-Like kinase-1 inhibitory activity of 10 μM. It was isolated along with debromohymenialdisine (5) and four novel dihydrohymenialdisine derivatives from the sponge Cymbastela cantharella [105].

There are several aspects to consider regarding kinase inhibitors such as whether they are ATP-competitive or non-competitive inhibitors and whether the compounds inhibit their reported enzymatic targets in cellular assays. However, the level of mechanistic detail and characterization of the kinase inhibitory activity of the compounds described herein varies greatly. Thus, herein those articles providing a higher degree of characterization are indicated in the Table 1 by an asterisk. A further issue is one of broader kinase selectivity profiling that would be useful to see addressed in the literature, both in terms selectivity of the inhibitors towards other kinases and towards other targets.

The search for kinase inhibitors from marine sources has proven extremely successful with the advent of compounds such as bryostatin-1 into pharmaceutical development, and others such as hymenialdisine (4) and manzamine (71) looking promising. In particular, marine sponges are a rich source of highly diverse chemical compounds including lipids, terpenes and alkaloids, enhanced by a high incidence of novel carbon skeletons, such as that of xestocyclamine A (1). Marine sponge metabolites have proven to be extremely potent against a range of kinase targets heavily involved in an increasing list of disease mechanisms including cancer, Alzheimer’s disease and atherosclerosis. Several kinase inhibitors such as fascaplysin (30) possess strong selectivity not only for specific kinase subtypes, but also for cancerous cells over healthy cells and are thus promising molecules in the development of new oncological pharmaceuticals. With new technological developments bringing access to previously unexplored marine environments such as the deep sea [106], it is certain that many more sponge metabolites with novel structures and potent kinase inhibitory activities will be discovered in the future. Furthermore, as our understanding of the mechanism and regulation of various kinases continues to grow, marine sponge-derived kinase inhibitors are destined to play an expanding role in the treatment of various diseases.