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 develops a new analogue of Mithramycin, selected from a family of compounds discovered by combinatorial biosynthesis of aureolic acid biosynthetic genes, whose Mechanism of Action consists 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.

Mithramycin is active against a variety of human cancers in experimental models and has been used clinically in the 1970’s, but discontinued due to its high toxicity. However, literature on the Mechanism of Action of Mithramycin has shown an explosive growth during the past decade and it is now at an all-time-high. In fact, Mithramycin is now back in clinical trials in two unrelated indications: Ewing sarcoma (NCT01610570) and non-small cell lung cancer (NCT01624090) targeting distinct Mechanism of Action on each histology (EWS-FLI1 fusion gene in sarcoma, ABCG2 transporter in lung cancer), reflecting the potential of this chemical class in the treatment of different types of cancer.

Regarding the mode of action, transcription 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 both ours and others show that the key event is activated transcription, which is triggered only in tumor cells, but not in healthy ones. More recently, the potential of transcription modulation has been described for tumors dependent on constitutive transcription, like GIST, driven by the oncogenic kinase c-kit.

EntreChem has selected EC-8042 based on its anti-tumoral in vitro and in vivo activity in mice models, demonstrating the potential for higher therapeutic window not only in xenograft models but in the NCI hollow fiber assay as well, ranking as one of the most active compounds on record. EntreChem has accomplished in vivo proof of concept in efficacy studies of a number of several human tumor models in mice.

More importantly, especially when developing natural product drugs, it is the in vivo EC-8042 safety profile. Our workflow allows evaluation of in vivo toxicity early in the process of drug discovery, thus EC-8042 was selected based on mice data showing one order of magnitude less toxicity than Mithramycin. In Dose Range Finding studies in rats and dogs, this toxicity differential has been verified. Moreover, pharmacokinetic data analysis in all the species tested allows projection of a human dose of EC-8042 also one order of magnitude higher than Mithramycin, providing an exciting opportunity to widen the therapeutic window and opening the door to expanded applications of this promising family of molecules and their pleiotropic mode of action.

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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 has focused its efforts in the Indolocarbazole chemical class, since several examples exist of natural and synthetic indolocarbazoles that have reached clinical stage research, indicating they are safe in humans. Our unique technology allows combinatorial biosynthesis of genes from the Staurosporine and Rebeccamycin metabolic pathways, providing a library of hybrid indolocarbazoles, whose Mechanism of Action consists on potent and selective inhibition of protein kinases. Since these analogs are much less promiscuous than Staurosporine, their toxicity in vivo enables further development. From this library, we have focused our development efforts on EC-70124, since its in vitro profile, confirmed by cellular experiments, indicates that its mode of action impacts tumors dependent of NF-kB activation, therefore potentially useful both in inflammation and cancer.

EC-70124 has been tested in several mice models for human cancer, among others glioblastoma multiforme, where it forces NF-kB dependent differentiation of cancer stem cells and prostate cancer, where it is particularly effective in tumors where there is overexpression of ESE1/ELF3 concurrent with NF-kB activation.

We are developing both intravenous and oral formulations, and the drug is active in animal models in either form, providing opportunities to optimize exposure accordingly. Dose Range Finding studies in rats and dogs have been carried out, and pharmacokinetic data shows circulating plasma levels well above those needed for therapeutic action in vitro, emphasizing the development potential of EC-70124 for oncology applications.

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