A rational, mechanism-based approach is key
in our development program.



MB231 cells with SUMO1 in green, F-actin in red and DAPI (nuclei) in blue. courtesy of Jim D. Sutherland (CIC bioGUNE).


development of SUMOylation inhibitors

SUMOylation inhibitors (SUMOi’s) will address unmet clinical need in the treatment of many cancers:

Hyper-SUMOylation and cancer
Emerging connections between protein SUMOylation and cancer have been reported. Elevated levels of SUMO components have been observed in several malignancies and are associated with poor patient outcomes. Multiple groups have provided evidence that inhibition of the SUMO pathway inhibits tumour growth in mouse models (reviewed in (Licciardello and Kubicek 2016) ). 
In addition, knockdown of SUMO-activating enzyme (SAE) confers synthetic lethality in tumours with high MYC (Kessler et al. 2012), (Hoellein et al. 2014), Notch1 (Licciardello et al. 2014) or mutant KRAS activity (Yu et al. 2015) ]. These findings suggest that SUMOylating enzymes may be potential therapeutic targets (He et al. 2017; He et al. 2015).

SumiQ develops mechanism-based covalent SUMOylation inhibitors:

Application of UbiQ’s Triple E platform
UbiQ, one of our founding companies has developed the Triple E platform, published in Nature Chemical Biology (2016), which exploits a reacting group that specifically traps the E1, E2 and E3 ubiquitylating enzymes (see figure). By adding this ‘hook’ onto ubiquitin itself or onto a small molecule, it has now, for the first time, become possible to monitor and/or block the activity of dozens of enzymes involved in protein ubiquitylation specifically. SumiQ is now conducting the first program based on this Triple E technology, by developing mechanism-based covalent SUMOylation inhibitors to treat cancer patients.

The key innovative elements of SUMOi’s developed by SumiQ include:

Choice of unique molecular target
Development of compounds inhibiting SUMOylating enzymes represents a revolutionary alternative strategy to direct targeting of oncogenic transcription factors, such as Myc, that do not contain any druggable domains. It has been shown that inactivation of SUMOylating enzymes in Myc-driven lymphoma results in a mitotic catastrophe and tumour cell death, leaving non-malignant cells unaffected (Hoellein et al. 2014).

Personalised medicine treatment
SUMOi-based therapy will be specifically developed for a high-risk relapsing/refractory patient population with confirmed Myc overactivation. 
Such a targeted treatment, based on specific genetic characteristics of a tumour, represents the ultimate personalised medicine approach. No personalised treatments currently exist for lymphomas, including diffuse large B-cell lymphoma (DLBCL).

Improved safety profile due to prodrug characteristics
Our SUMOi’s are inert and only become active upon activation by the primary target enzyme (SUMO E1). 
This prodrug characteristic offers a significant safety advantage.

Achieving improved antitumour efficacy in a defined difficult-to-treat patient population by targeting a primary oncogenic pathway, represents a breakthrough in cancer treatment:

Example: treatment of resistant DLBCL tumours
Non-oncogenic addiction of diffuse large B-cell lymphoma (DLBCL) on SUMOylation: The malignant phenotype of treatment-resistant DLBCL tumours is dependent on a feedback loop involving Myc overactivation and hyper-SUMOylation of downstream proteins (Hoellein et al. 2014). For SUMOylation, a sequential action of conjugating enzymes (SUMO E1, E2 and E3) is required in order to ligate SUMO to a specific protein. SUMOylation inhibitors developed by SumiQ inhibit simultaneously two conjugating enzymes, E1 and E2, thereby preventing transfer of SUMO to substrate proteins and disrupting the Myc/hyperSUMOylation loop in resistant DLBCL.