oa Editorial [Hot Topic: Targeting G Protein and Phosphorylation Dependent Signalling Molecules for Anticancer Therapy (Guest Editor: Jeyanthy Eswaran)]

G-protein and phosphorylation dependent signalling network are the major signalling pathways that control several fundamental cellular processes. Therefore understanding the biology and the molecular mechanism of these molecules allow us to identify possible drug targets. Although there has been an incredible research focus on understanding the onset and progression of cancer, the search still continues across various avenues to come up with novel therapeutics and improvised strategies to combat cancer. Here, the aim of this hot thematic issue is to highlight emerging G-protein and phosphorylation dependent signalling molecules that are potential anticancer drug targets as well as “drug like” molecule development strategies. During cancer invasion, the first line of defence is conceded when the tumour associated antigens are misrecognised as self-associated entities. This happens mainly because the host T cells that tackle the tumoral cells through specific immune responses accidently results in uninhibited tumour cell progression. Therefore, understanding the mechanism of immune system recognition and elimination of “cancer triggers” at the molecular level through immunosurveillance is essential for the development of novel, anti-cancer strategies. This concept is extensively discussed by Escors and coworkers where they detail how the constitutively activated MAP kinase, NF-κB and Toll like receptor pathways provide effective mode of cancer immunotherapy. The use of constitutive activators of TLR signalling, NF-κB and MAPK pathways appears promising in preclinical models enabling the possibility of this line of attack to be complementary to the much prevalent but classical current radio and chemotherapies. The identification of tumor associated antigens (TAAs) and the increasing knowledge of Toll-like receptors and other signal transduction pathways provide the basis for this approach, and Arce et al discuss this in detail in their article. Using kinase inhibitors as anticancer agents have been the most popularised approach. However recent studies from various groups using structural genomics and other approaches have provided in depth insight into the molecular mechanism and regulation of tyrosine dephosphorylating PTPases. The comprehensive overview provided by Tremblay and colleagues in the review titled ‘Impact of oncogenic protein tyrosine phosphatases in cancer’ offer extensive account of various PTPs that are deregulated in specific types of cancers and critical rationale that enables PTPs as cancer targets. In addition, Hardy et al also provides functional overview of broad array of PTP family members, with their biological significance in oncology, and how recent structural and functional characterisation enhances the understanding of PTP family molecular mechanism and substrate specificity. Apart from the kinases and phosphatases, another central player, the GTPases function as integral components in several signalling cascades. More interestingly, the emerging atypical GTPases family with altered domain architecture, tertiary structures, and guanine nucleotide binding properties highlight the versatile nature and diversity found in the fundamental mechanism such as GTP hydrolysis. Soundararajan et al review the members of this family and focuses mainly on two families of atypical Ras GTPases, the RGK GTPases and centaurin isoforms, which modulate various signalling nexus of the cancer therapy targeted PI3 kinase-AKT-mTOR signalling pathway. The role of RGKs in cyctoskeletol remodelling and the biological function of centaurin in calcium signalling and cancer development and neuronal functions is discussed elaborately. The unusual catalytic motifs and structural elements are discussed in the context of classic GTPase, H-Ras. In summary, this review provides comprehensive report on the recent progress in the atypical GTPases field prompting the field to focus on “contemporary” functions of the atypical GTPase domain. In addition to the identification of “druggable signalling modulators”, developing novel anticancer agents is also proved to be an integral component of cancer therapeutics development. Recent focus involving more systematic approach to screen phytochemicals using high throughput screening by cancer researchers have placed them as promising class of entities for alternative drug molecule development. Chitra Mandal and colleagues have discussed how natural products derived small molecules can be effectively used as specific anti-cancer agents that target signalling pathways. In this article, the authors categorize the extracts and their sources along with the possible mechanisms of action in cancer chemotherapy generating an excellent catalogue of compounds and signalling pathways they may interfere. Further, the anticancer agents derived from medicinal plants that exhibit remarkable chemo-preventive and anti-tumorigenic properties detailed in this review provides us convincing evidence for the tremendous potential these unexplored agents offer towards tackling apoptotic pathways in various cancer types. Another well-established, successful drug development concept is the fragment based drug design, which has been tested and proved to be effective over the past decade. Turnbull and Boyd in this issue systematically provide an overview of the principle, concept development, and screening techniques employed for fragment interaction detection. Identifying weak interaction between the fragment and the target molecule is identified as a challenge in this approach. Turnbull et al discusses the strengths and pitfalls of current arsenal of methodologies such as nuclear magnetic resonance (NMR), X-ray crystallography, surface plasmon resonance (SPR), thermal shift assay (TSA) and high concentration screening (HCS). Further, a comprehensive case study of inhibitor development using fragment based drug design approach for various targets including Aurora kinase, PDK1, Pin1, Bcl-2, Hsp90, PKB, CDK, uPA, BRAF kinase, BCR-Abl, Chk-1 and JAK2 is outlined highlighting the successful establishment of this approach. In keeping with that, there are several FBDDderived compounds now entering into various stages of clinical trial. Thus, Turnbull et al provides a timely, comprehensive overview on the application of fragment based drug design process that would expand the chemical diversity and druggable window of anti-cancer agents. In summary, the presented hot thematic issue brings forth unexplored target areas in the rapidly moving field of G-protein and phosphorylation dependent signalling, current drug screening strategies as well as naturally occurring anti-cancer agents.