What we do
Dual inhibition of G9a and CDK-9 to challenge Myc-overexpressing cancers
Myc is one of the most prominent and best characterized proto-oncogenes with Myc overexpression observed in various cancers, including prostate, ovarian, breast and NSCLC. This largely results from gene amplification of the myc gene.
Myc is a central switch that turns normal cells into cancer cells in two principal ways:
- Myc binds to positive transcriptional enhancer elements resulting in the general amplification of mRNA transcription, consequently resulting in more protein mass that sustains the extended needs of tumour cells.
- Myc also binds specifically to negative enhancer elements in the promoters of certain tumour suppressor genes, e.g. Thus, increased levels of Myc suppress important tumour control checkpoints, thereby resulting in de-differentiation of normal into tumour cells.
G9a is a protein-lysyl-methyl transferase that was identified as being responsible for the methylation of critical lysine residues of histones. In addition to this important function, G9a also methylates Myc to enhances its activity. Notably, genetic knockout of G9a or pharmacological inhibition of G9a results in a restoration of Myc-dependent transcription of tumour suppressors without having an impact on the positive amplification function of Myc on general transcription.
In order to address the pro-tumorigenic function of Myc in cancer, we will inhibit CDK-9, a protein kinase that ensures RNA polymerase II “read-through” of mRNA early transcripts that are subject to additional checkpoints for full transcription. C-myc is one of those transcripts that needs CDK-9 dependent “clearance”. Consequently, inhibition of CDK-9 leads to a reduction of c-myc mRNA to below levels required to support the growth of cancer cells.
LXR stimulation by potent agonists reduces myeloid-derived suppressor cells (MDSCs) in the tumour microenvironment
One key reason why checkpoint inhibitor immunotherapy frequently fails in solid cancer treatment is that the tumour excludes aggressive immune cells from entering it. Such “cold”, i.e. immune-excluded, tumours often harbour myeloid-derived suppressor cells (MDSCs). These are innate immune cells that secrete cytokines and other signals to either prevent aggressive CD8-positive T-cells from entering and attacking the tumour or they switch CD8-positive T-cells into cancer-permissive regulatory T-cells (Tregs).
LXR is a nuclear receptor, which are ligand-activated transcription factors modulated by bioactive lipids or steroids, with LXR activity controlled by oxysterols. LXR is a master regulator of de novo lipogenesis in various tissues but foremost in the liver. Historically, LXR has been regarded as a drug target to treat atherosclerosis (by agonistic stimulation) or even fatty liver disease (by antagonistic blockade of lipogenesis) and WMT scientists have been involved in both approaches. Recently, a US team uncovered an unexpected link between LXR and MDSCs. LXR activation – amongst various other lipid and lipoprotein components – produces Apolipoprotein E (Apo E) and releases it into the bloodstream. Apo E binds to the LRP8 receptor on the surface of MDSCs. Once LRP8 is liganded, MDSCs are triggered to go into apopotosis, which eliminates their immunosuppression within the tumour microeonvironment (Tavazoie et al, Cell 172(4):825-840 (2018)).
This reduction in MDSCs changes the immunosuppressive milieu in the “cold” tumour to permit an inflow of CD8+ T-cells and other tumour-attacking immune cells, which ultimately clear the growing solid tumour.
Pirin modulators that block NF-kappa B dependent transcription – an entirely new way to reduce inflammation in COVID-19 and in cancer
Pirin is an evolutionary conserved, non-heme iron containing protein. It functions as a redox-sensor and as a transcriptional coactivator. When cells are in a normal “unstressed” condition, Pirin is in the Fe(II) state and is transcriptionally silent. When cells sense redox stress (tumour cells under ROS stress, immune cells under cytokine activation), the iron atom in Pirin is oxidised into the Fe(III) state which induces conformational changes that convert Pirin into an active transcriptional coactivator.
Fe(III) Pirin then activates NF-kappa B dependent transcription. NF-kappa B is amongst the best characterized pro-inflammatory transcription factors and is involved in the production of many key proinflammatory cytokines, e.g. TNFalpha, IL-6 and others. Fe(III) but not Fe(II) Pirin supports NF-kappa B in this role.
We have identified Pirin ligands that bind to Fe(III)-Pirin but turn it into the Fe(II) conformational shape, so rendering Fe(III)-Pirin transcriptionally incompetent. Thus, we have discoverd a solution to the long-sought goal of inhibiting NF-kappa B. Switching off Fe(III) as an NF-kappa B coactivator is a surprisingly effective means to shut down proinflammatory cytokine production nearly completely.
Pirin conformational switch modulators have various potential applications in chronic inflammatory diseases, in sepsis and others but currently we see the most immediate medical needs in treating NF-kappa B dependent cancers and in alleviating the cytokine-storm induced by COVID-19 .
In SARS-CoV-2 infected cells, NF-kappa B is a key initiator of the cytokine response (Neufeldt et al., bioRxiv (July 2020) https://doi.org/10.1101). We collaborate with the group in Heidelberg that has identified the involvement of NF-kappa B in SARS-CoV-2 and test for the application of our Pirin ligands in the COVID-19 related cytokine storm (Severe Acute Respiratory Syndrome = SARS).
In parallel, we also pursue the development of Pirin ligands as a treatment for NF-kappa B-dependent cancers. Multiple Myeloma (MM) is a plasma cell cancer that is well characterized to be dependent on an overly active NF-kappa B transcription. The two most effective treatments of MM, Bortezomib and Thalidomide, converge to limit NF kappa B signalling and validate the favourable impact of inhibiting NF kappa B activity in MM.
Pirin modulators are a new and exciting option for the treatment of MM and other inflammation-driven cancers.
Who we are
Yves GuillermetChief Excutive Officer of WMT
Yves has more than 25 years experience in general management with increasing responsibilities in human resources, controlling and finance, project management and consulting…
Dr. George ReidDirector Drug Discovery Biology
George has more than 25 years experience in academic research as well as in applied drug discovery. He spent long years at the EMBL and as group leader at the IMB in Mainz…