MB231 cells with SUMO2 in red and DAPI (nuclei) in blue. courtesy of Jim D. Sutherland (CIC bioGUNE).

SUMO science

SUMOylation (Small Ubiquitin-like MOdifier conjugation) is a posttranslational modification that regulates function, subcellular localisation, and/or expression of a wide-variety of proteins. SUMOylation of proteins is controlled by an enzymatic cascade consisting of an E1 (activating) enzyme, an E2 (conjugating) enzyme  and (in some cases) an E3 (ligating) enzyme (Figure 1).

The Triple E warhead (Figure 2, Nat. Chem. Biol. 2016, 12, 523) is a proprietary (Adenylation enzyme inhibitors. Application WO/2016/032332 and NL2015/050596) and characteristic part of the SUMOi’s developed by SumiQ. The Triple E warhead is inert at physiological pH, but once activated by the SUMO E1 enzyme it is capable of trapping the SUMO E1 and subsequently E2 enzyme in a covalent and mechanism based manner (Figure 2). Our target-activated prodrugs are designed to mimic the C-terminal part of the SUMO protein by using highly innovative, rational design.

Non-oncogene addiction describes a dependence of malignant cells transformed by oncogenes (such as Myc) on specific physiological pathways (e.g. SUMOylation) to perform cellular functions essential for tumour growth. By definition, these pathways are not mutated (non-oncogenic) but operate at a critical level close to exhaustion. Targeting these pathways selectively kills tumour cells while sparing normal cells that can resort to parallel pathways.

Figure 1

Figure 2