Project Portugal 2030

Summary

This project aims at developing PARP1/PI3K DIs as a strategy to target two crucial cellular pathways involved in DNA repair and cancer cell survival. The rationale behind this approach lies in the expected synergistic effects and enhanced therapeutic benefits that may arise from simultaneously inhibiting these two enzymes, resulting in superior anticancer effects compared to targeting either pathway alone. The overlapping functions of these two enzymes in DNA repair – PARP1 participates in the repair of single-strand breaks and PI3K is implicated in homologous recombination repair – could impair multiple DNA repair pathways, making cell more susceptible to DNA damage-induced cell death. Moreover, the likelihood of cancer cells developing resistance to treatment may be reduced, as the dual inhibition disrupts multiple survival mechanisms. The dual-inhibition approach allows a more personalized and targeted approach. In fact, some tumors exhibit genetic alterations or dysregulation in both PARP1 and PI3K pathways and the DIs may be particularly effective in the treatment of these specific subtype of cancers. On the other hand, selectivity for cancer cells may be better. It is known that cancer cells often rely on multiple survival and growth pathways simultaneously. DIs may be more selective for cancer cells, as normal cells may be less dependent on both pathways concurrently. This selectivity could potentially reduce side effects associated with treatment, improving the patient’s quality of life. Despite these advantages, the literature review and market analysis highlight a significant gap in the supply of effective treatments that simultaneously address both PARP1 and PI3K pathways. Innovation in this project lies in the answer to this unmet need in the field of cancer therapy. In fact, the literature describes only three potential PARP1/PI3K DIs that didn’t reach the market. Moreover, none of these DIs contain the pyrazole or indazole nuclei in their structure despite several studies in the literature that show the potential of these compounds to individually inhibit PARP1 or PI3K enzymes. The novel approach of these project is to explore, for the first time, the potential of pyrazole and indazole, two privileged structures in medicinal chemistry, in the development of novel PARP1/PI3K DIs. Previous studies of our group, involving synthesis, computational docking and molecular dynamics studies and analysis of structure-activity relationship (SAR), allowed the identification of pyrazole-based compounds that are very promising as PARP1 inhibitors. In silico ADMET sudies allowed us to confirm the safety profile of these compounds although these results need to be confirmed though in vivo studies aiming to investigate potential side effects on organs and tissues, ensuring compounds safety for clinical development. This project will allow the advancement of our previous studies to a higher level. Anticipated challenges in drug development and testing will be overcame including alternative methodologies for the synthesis of the compounds and alternative bioassays. This is an innovative and ambitious project that involves collaboration between experts in different fields, such as organic chemistry, biochemistry, molecular biology reflecting an interdisciplinary approach. This can enhance the project's ambition and impact by leveraging diverse perspectives and expertise.