Cancer has been identified as a group of diseases characterized by abnormal cell growth. In eukaryotic cells, the nucleolus is the region of the nucleus that constructs ribosomal subunits. Polymerase 1 transcription site has been used as the marker to particular aggressive tumours seen when the nucleoli increases in size and number. The nucleolar size correlates with the level of rRNA synthesis, which is transcribed by RNA polymerase 1 (RNAP1) during the initial stage of ribosome biogenesis. In recent years the rRNA transcription has emerged as novel target for anti-cancer therapy and specific RNAP1 transcription inhibitor are currently undergoing clinical trials for anti-cancer therapy. Thus, the proposed therapeutic strategies for solid tumour growth or inhibition of cancer cell proliferation is the selective inhibitor RNAP1 transcription. The currently available inhibitors are characterised by a different mechanism and different levels of genotoxicity. Two drugs, (CX-5461 and PMR-116) are small molecules and selective inhibitor of RNAP1 transcription which have moderate effect on transcription by other nucleolar polymerases and protein translation. CX-5461 inhibits transcription by displacing essential promoter recognition factor SL1 thus preventing an initiation of transcription. PMR-116 demonstrated a great potential as RNAP1 inhibitor, is characterized by low cytotoxity and very high anti-cancer effect. However, the exact molecular mechanisms of RNAP1 inhibition is unknown. Therefore, this experiment aims to identify the stage of the transcription cycle affected by PMR-116 by using a combination in vitro and vivo based assays. Also, to determine the drug target into the molecular mechanism of PMR-116 by using biochemical methods including Isothermal Titration Calorimetry (ITC).

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