EC-70124: oral multi-kinase inhibitor targeting both tumor and cancer stem cells in acute leukaemias and solid tumors (FL3-PIM-SYK triple inhibitor for AML)

Discovery and Development of kinase inhibitors represents a major effort in R&D for pharmaceutical companies nowadays, as a result the number of publications on this topic is at an all-time high. The mainstream 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 of natural and synthetic indolocarbazoles have reached clinical trials, indicating they are safe in humans. Our unique core technology allows combinatorial biosynthesis of genes from the naturally occurring Staurosporine and Rebeccamycin, providing a library of hybrid indolocarbazoles, whose Mechanism of Action is based on potent but more selective kinase inhibition as compared to the all-natural hit compounds. Since these analogs are much less promiscuous than Staurosporine, their toxicity in vivo enables further preclinical development.

EntreChem has selected EC-70124 from this library for development, since the biochemical in vitro profile, confirmed by cellular experiments, indicates that its mode of action impacts solid tumors dependent of pathways like NF-kB, Akt/mTOR, JAK/STAT, and Acute Leukemias dependent on FLT3, PIM and SYK. Therefore, EC-7014 is potentially useful both in solid and hematological tumors.

Some of these pathways are known to be present not only in the bulk of the tumor, but the cancer stem cell population as well. This provides the opportunity to target both populations with the same molecule, unlike traditional chemotherapy and other targeted approaches. Early examples of this potential have been demonstrated by EntreChem in several murine models, 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 overactivation of STAT3 concurrent with NF-kB, a mechanism shared by the cancer stem cells as well.

More recently, we have described EC-70124 as the first in class triple Flt3-Pim-Syk inhibitor for Acute Myeloid Leukemia (AML) with superior metabolic and PPB profile. In AML, earlier efforts focused on a single target (FLT3), resulting in the approval of Midostaurin by Novartis, developed from the same chemical class as EC-70124. Next-generation drugs in this space recognize the value of hitting additional targets, and several programs based on dual inhibition are in mid-stage clinical trials (dual FLT3-PIM, FLT3-SYK, FLT3- PDGFR).

The oral formulation developed by EntreChem is active in animal models of both solid tumors and leukaemias. Dose range finding (DRF) and IND-enabling toxicity studies have been carried out, and pharmacokinetic data shows plasma levels well above those needed for therapeutic action in vitro. Importantly, the protein plasma binding in humans is several times lower that clinically proven inhibitors of its class, emphasizing the potential of EC-70124 for oncology applications.

EC-70124 boasts a strong publication record in peer-reviewed, high impact journals. Highlights of EC-70124 profile:

  • EC-70124 targets kinases involved in cancer development, according to data from the Ambit, Proqinase and Carna platforms. Targets include Flt3, JAK2, SYK, CHK1, PIM, Aur, IKK.
  • EC-70124 targets cancer stem cells, as proven, among other data, by sphere forming assays both in vitro and ex vivo from tumor xenografts treated with the drug. This is an important feature that sets apart EC-70124 from traditional chemotherapy.
  • Pharmacodynamic studies show EC-70124 hits targets in vivo at efficacious doses for xenograft treatment. For example, NF-kB activity shuts down after a drug pulse is delivered orally.
  • EntreChem has demonstrated multiple in vivo proof of concept with EC-70124, showing high efficacy in human tumor mice models: 70-90% tumor growth inhibition (TGI) or partial to full regression, together with significant survival benefit. The most impressive response is observed in hematological tumors, specifically Acute Myeloid Leukemia (AML), including full regression and permanent cures. Solid tumors include glioblastoma, prostate cancer, triple negative breast cancer and colon cancer. Further details in the publication list.