Novel inhibitor of DNA ligase IV with a promising cancer therapeutic potential.

ABSTRACT

Cancer is a dreaded disease where effective and cheap drugs are wanting. A large body of research is trying to identify anti-cancer molecules from nature, including plants, marine organisms, microorganisms, etc., and to ultimately synthesize promising molecules in the laboratory. Antibodies to tumour antigens/ receptors, microtubule inhibitors and DNA linking agents have been developed and used as drugs. Today the thrust is on identifying druggable molecules within the tumour cell. Small molecule inhibitors, targeted against crucial enzymes such as kinases, has led to the discovery of important anti-cancer drugs such as Glivec and Gefitinib. There is a great deal of interest in the development and use of therapeutics that target DNA repair pathways. Raghavan and his group chose Ligase IV as their target in the DNA repair pathway (Srivastava et al. 2012) Maintenance of genomic integrity is essential for cell homeostasis. Efficient repair of DNA damage ensures genomic stability. However, cancer therapies such as radiation and chemotherapy function by damaging genomic DNA, by specifically targeting rapidly dividing cancer cells, ultimately leading to cell death. Most of the cancer cells are repair-deficient, thereby providing a therapeutic opportunity to target DNA repair machinery. Although radiation and genotoxic drugs are initially effective in arresting tumour growth and reducing tumour burden, resistance and disease progression eventually occur. The resistance is acquired due to constant selection pressure by the therapeutics. Genetic mutations in the DNA repair genes are not only the initiating event in a cancer cell but also its limitation because the mutated gene function is often required by the cancer cell to maintain its own survival. This limitation has been exploited to specifically kill the tumour cells by targeting the mutated DNA repair gene while sparing the normal ones, a concept known as ‘synthetic lethality’ (Kaelin 2005). One of the main DNA damage repair pathways is double strand break (DSB) repair, which includes nonhomologous end joining (NHEJ) and homologous recombination (HR). It is plausible that targeting the molecular machinery driving the DNA damage repair (DDR), particularly NHEJ with small molecule inhibitors, will effectively enhance the efficacy of current cancer treatments that generate DNA damage and exploit synthetic lethal interactions. Radiation therapy and chemotherapy leads to DSB where NHEJ plays a major role in providing resistance to these agents in a cancer cell. The initial inhibitor L189 against Ligase I, III and IV reported in literature was non-specific (Chen et al. 2008). Raghavan and his group overcame this limitation by targeted design using specific docking of Ligase IV and comparing with L189 (Srivastava et al. 2012). The clever strategy led to the discovery of a novel specific inhibitor SCR7 for Ligase IV. Using elegant experiments on cell lines and mouse model the authors convincingly demonstrated that SCR7 was a specific Ligase IV inhibitor. SCR7 inhibits end joining of double strand breaks in diverse cell types resulting in tumour regression by activation of p53 mediated apoptosis (figure 1). Notably SCR7 treatment did not result in any adverse effects in mice and did not inhibit Ligase III. The authors have envisaged and addressed the likely limitations of SCR7 as a potential anti-cancer drug in humans and have proposed that cancer cells, due to their higher replication, high DNA damage rate and defective cell-cycle checkpoints, will be more sensitive to SCR7 compared to surrounding normal tissues (Srivastava et al. 2012). This may also reduce the possibility of resistance to SCR7. The therapeutic efficacy of SCR7 could be enhanced by specific delivery of SCR7 to the tumour tissue and as adjuvant cancer therapy.