Deregulation of transcription factor activity is an important event in the pathogenesis of cancer. Compounds able to block overactive transcription factors and modulate gene expression are very attractive therapeutic agents, since just one compound could address multiple drug targets, avoiding the complexity of combination therapy of single target drugs.

EntreChem is developing a new analogue of Mithramycin (MTM), selected from a family of compounds discovered by combinatorial biosynthesis of aureolic acid biosynthetic genes, whose Mechanism of Action (MoA) consist of selective binding to GC-rich DNA sequences, specifically to the site of union of the transcription factor Sp1, which is itself overexpressed in many types of tumor cells and causes the overexpression of its regulated genes, mainly VEGF and c-myc.

MTM is active against a variety of human cancers in experimental models and has been used clinically in the 1970's to treat testicular carcinoma as well as hypercalcemia in patients with metastatic bone lesions and Paget’s disease. However, its current clinical use is limited by its severe side effects.

Sp1 transciption factor inhibition has been underexploited as drug target perhaps due to the established notion that a basal transcription factor will never work as drug target. However, recent data from ours and others show that the key event is activated transcription, which is triggered only in tumor cells, but not in healthy ones.

EntreChem has selected the candidate compound based on its antitumoral in vitro activity, but most importantly on its toxicity profile in mice. The candidate shows an order of magnitude less toxicity than MTM, opening the door to a revival of this family of compounds, since toxicity has historically limited its widespread use. EntreChem has accomplished in vivo proof of concept in efficacy studies of a number of human tumor models in mice.

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Discovery and Development of kinase inhibitors represents a major effort in R&D for pharmaceutical companies nowadays. The goal is to develop selective and potent inhibitors of kinases involved in signal transduction pathways related to a variety of diseases, especially those unlocking new drug targets.

Entrechem is developing a new molecule, an analogue of Staurosporine, selected from a family of compounds discovered by combinatorial biosynthesis of indolocarbazole biosynthesis genes, whose Mechanism of Action (MoA) relies on potent and selective inhibition of Ikkb kinase, a validated target of the IKK complex, and as such, a disruptor of the NF-kB signaling pathway, well known by its involvement in inflammation and cancer diseases.

The candidate molecule has been submitted to target validation in vitro and in vivo proof of concept of our Ikkb inhibitor in a model of human cancer, so the first application of this promising inhibitor belongs to the field of oncology. To the best of our knowledge, no Ikkb inhibitor has entered clinical trials yet, therefore EntreChem's Ikkb inhibitor represents a great opportunity to develop a first in class therapy. Also, since NF-kB pathway is involved in many other diseases, it is reasonable to presume that other applications could be developed for this Ikkb inhibitor.

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