Development and testing of small molecule NUDT22 inhibitors for uses in cancer

The INTEGRATA network –“Integrating chemical and biological approaches to target NAD production and signaling in cancer” – aims at providing a group of early stage researchers (ESRs) with a highly interdisciplinary and intersectoral training in drug discovery, focusing specifically on NAD production and on NAD/nucleotide signaling as targets for the development of new cancer therapeutics. INTEGRATA will train 14 PhD students in an overarching training programme involving training-by-research, joint courses of technical, scientific and transferrable skills, participation to public scientific events, and an intense intersectoral networking exchange plan (secondments). The INTEGRATA consortium encompasses academic institutions, research centers, and SMEs, all with proven experience in higher education and training, and state-of-the art scientific and technical expertise and infrastructures.

The research activities implemented in INTEGRATA have the following objectives:

1. To develop new agents for interfering with NAD biosynthesis in cancer cells [NAMPT, NAPRT, inhibitors and Ab drug conjugates (ADCs) to target NAMPT inhibitors to multiple myeloma (MM), B-cell lymphoma and AML cells], neutralizing monoclonal antibodies
(mAb) against eNAMPT and eNAPRT and NAD/nucleotide signaling inhibitors (SIRT6, NUDT22, CD73, and TRPM2 inhibitors).
2. To perform an extensive testing of the newly generated NAD biosynthesis and NAD/nucleotide-signaling inhibitors (and of inhibitors that have been recently developed by partners from the Consortium) in cultured cells and in in vivo cancer models, including models for assessing angiogenesis and cancer cells’ metastatic spread.
3. To conduct pre-formulation/fingerprinting, formulation and pharmacokinetics (PK) studies with the newly produced NAD biosynthesis and NAD/nucleotide-signaling inhibitors.
4. To define anticancer activity and potential toxicities of the newly generated agents, as well as of a dietary approach based on a NA-free diet w/ or w/o antibiotics (to reduce NAPRT activity) in relevant in vivo cancer models.

Each of the 14 ESRs will be enrolled in the PhD programme of the beneficiary’s organization (the beneficiaries which do not award PhD will establish agreements with local and international universities that can provide the degree) and will participate in the network’s training activities and work placements at the laboratories of the participating academic and industrial partners. In addition, the training programme of the recruited ESRs will be implemented with regular meetings and workshops within the INTEGRATA network.

The project offered by the laboratory of Professor Thomas Helleday will be to elucidate how NUDT22 is involved in nucleotide metabolism and the response of cancer cells to replicative stress and to identify and test NUDT22 inhibitors. Potent and selective small molecule inhibitors of NUDT22 will be developed and utilized to probe biological function(s). The newly developed NUDT22 inhibitors will be tested in cultured cancer cell lines, but also in non-cancer cells, for their effects on cell proliferation, replication, cell viability and susceptibility to nucleoside analogue therapies and radiotherapy. The preclinical pharmacology of the NUDT22 inhibitors will be defined and their in vivo anti-cancer effects will be assessed in xenografts.