Helquats, c-myc downregulation small molecules

Challenge:

Cancer treatment is a long-standing problem of global health. Currently, there are several novel and promising strategies being developed to combat cancer. One of them is based on the down-regulation of c-myc expression. Such a down-regulation can be achieved through RNA interference or stabilization of the G-quadruplex (specific DNA motif) in the c-myc promoter.

Pipeline products show the relevance of such strategies: c-myc anti-sense RNA DCRM-1711 (biologics in Clinical phase II), and G-quadruplexes stabilizing quarfloxin (discontinued in Clinical phase II) targeting various indications like solid tumors, B-cell chronic lymphocytic leukemia, lymphoma, and neuroendocrine carcinoma.

Quarfloxin did not succeed in Clinical phase II due to bioavailability problems, therefore the G-quadruplex targeting remains a promising line of anti-cancer research and novel G-quadruplex binding agents are among attractive drug candidates. We developed a unique type of structures showing strong and selective G-quadruplex stabilization, lacking the solubility problem of quarfloxin and belonging to the small molecules category.

 

Technology:

fig1

We developed a novel class of selective G-quadruplex stabilizing ligands – helquats, which show promising bioactivity at low micromolar concentration in cell based assays. The helquat derivatives exhibit antiproliferative activity in selected cancer cell lines over-expressing c-myc and show an encouraging toxicity profile comparable to those of quarfloxin. Furthermore c-myc G-quadruplex specific effect is confirmed by two Burkitt lymphoma cell lines Raji and CA-46, representing the ultimate model of c-myc expression influenced by the presence (Raji) or absence (CA-46) of G-quadruplex motif controlling gene expression. Mice toxicity studies are underway with favorable preliminary results.

Commercial opportunity:

The project is offered for co-development and/or licensing.

 Development status:

Lead optimization, in-vitro testing and preliminary toxicology.

 Patent situation:

Compounds and their use are protected by two patent applications with priority dates 2013 and 2014 (PCT).

Results preview:

 C- myc results

                                  

 

The stabilization of G-quadruplex in the c-myc promoter by a ligand leads to down-regulation of c-myc expression and thus decreased cell proliferation and viability.