EC-8042: a transcription modulator mithralog, one order of magnitude less toxic than parent mithramycin, targeting both tumor and cancer stem cells.

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 targets, avoiding the complexity of combination therapy of single target drugs.

EntreChem develops analogs of Mithramycin (MTM), discovered by combinatorial biosynthesis of aureolic acid biosynthesis genes. The Mechanism of Action (MoA) consist of selective binding to GC-rich DNA sequences, such as the site of union of the Sp1 transcription factor, which is itself overexpressed in many types of tumor cells and causes the overexpression of its regulated genes, among them VEGF, c-myc, ABCG2, PTEN-Akt, survivin, TGF-ß.

MTM has been used clinically since the 1970’s, but discontinued due to high toxicity, causing a diminishing literature output in the 1980s and 1990s. On the other hand, Sp1 is a target supported by a significant body of research (>1000 papers), especially in the last 15 years. As a result, since 2000 literature on MTM has been growing, paralleling that of Sp1, its historically recognized target.

Transcription factor inhibition has been underexploited as drug target since many transcription factors are considered undruggable targets, involving difficult to model protein-DNA interactions and hard to address by synthetic chemistry-based Drug Discovery.

In the case of Sp1, slow progress is additionally due to the established notion that a basal transcription factor will never work as a drug target. However, recent data from us and others show that the inhibited event is activated transcription, which is triggered only in tumor cells, but not in healthy ones.

Recently it has been discovered that, while Sp1 is overexpressed in many tumors and frequently addressed by MTM in pharmacological studies, MTM and its analogs show strong activity in tumors with altered transcription driven by other mechanisms not necessarily involving Sp1.

Indeed, MTM was tested recently in clinical trials in two cancer indications (Ewing sarcoma and non-small cell lung cancer) targeting different modes of action (EWS-FLI1 fusion gene in sarcoma, ABCG2 transporter in lung cancer), reflecting the potential of this natural product chemical class in the treatment of cancer. However, toxicity and poor PK limit the clinical use of MTM, so mithralogs with improved therapeutic window remain attractive solutions to unmet medical needs represented by tumors with deregulated transcription.

EntreChem has selected EC-8042 based on its antitumoral 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.

EC-8042 boasts a strong publication record in peer-reviewed, high impact journals. Highlights of EC-8042 profile:

  • EC-8042 targets Sp1, Sp3, VEGF, ABCG2: synergistic effect by hitting transcription factor networks, angiogenesis pathway and drug transporters.
  • EC-8042 inhibits Sp1 and downregulates Cancer Stem Cell gene signature. Importantly, widely used anthracycline doxorubicin upregulates such signature. Targeting stem cells is an important feature that sets apart EC-8042 from traditional chemotherapy.
  • EC-8042 has accomplished multiple in vivo proof of concept, showing high efficacy in human solid tumors mice models (70-90% TGI) and survival benefit. In particular, pediatric cancers like Ewing sarcoma and rhabdoid tumor are among the most spectacular in vivo results, representing also examples of targets not involving Sp1, but other altered transcription targets (EWS-FLI1, and SWI/SNF respectively).
  • A key aspect, especially in natural product drug development, is the in vivo toxicity profile. Our work flow allows identification of low toxicity analogs early in the process of drug discovery, thus EC-8042 was selected since it shows one order of magnitude less toxicity than MTM. In dose range finding (DRF) studies in rats and dogs this toxicity differential has been verified, as well as in the IND-enabling pivotal tox studies. Pharmacokinetic data analysis in all the species tested allows projection of a human dose of EC-8042 also one order of magnitude higher than MTM, 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.