Small molecules hits, and companion diagnostic, selective for the ATP generating activity of NUDT5.

We are developing lead compounds that eventually could be used to complement poly ADP-ribose polymerase therapy or as a treatment on itself as an alternative treatment option to treat primary and metastatic cancers.

Technology:

Recurrence and metastasis in advanced cancer account for the majority of cancer deaths due to insufficient effective therapies or the development of chemo- and targeted therapeutic resistance. This is clearly demonstrated by poly ADP-ribose polymerase 1 (PARP1) inhibitors, currently used clinical tools against ovarian (Brca +/-), Brca+ breast and other cancers), where as many as 20-30% patients become resistant to them. In this approach, the ATP generating activity of the enzyme NUDT5 in cancer cells, downstream in the PARP pathway, is targeted to inhibit cancer cell proliferation as the therapeutic strategy. This target is also critical for cancer cell/stem cell survival and migration initiating metastatic invasion, colonization and recurrence and so its targeting can be an effective strategy to address the drawbacks outlined above.

The CRG team identified small molecule hits that specifically inhibit the ATP-generating activity of NUDT5 without affecting its canonical activity. In collaboration with the International University of Catalonia and the Spanish National Cancer Research Centre - is now working on multifactorial optimization of the hit molecules.

Advantages:

• Close complementing PARP1-ATP-NUDT5 inhibitory actions in the same pathway enhancing the anti-cancerous effect:​
  • ATP-NUDT5 inhibition directly, and PARP1 inhibition indirectly, depletes the source of ATP;​
  • NUDT5, next to PARP, is required for DNA repair for cancer cell survival, inducing synthetic lethality.​
• ATP-NUDT5 inhibitor is the preferred partner of a PARP inhibitor allowing its significant dose reduction leading to reduced toxicity and development of resistance against it.​
• ATP-NUDT5 is critical for both primary cancer cell survival/growth, and cancer stem cell survival and migration initiating metastatic invasion, colonization and recurrence.​

References:

Wright RH., Lioutas A., Le Dily F. et al. ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling. Science 3 352 (2016). https://doi: 10.1126/science.aad9335