Since 2014, when olaparib received the FDA approval for ovarian cancer, Poly-ADP-ribose polymerase (PARP) inhibitors have gained a key role in the field of precision oncology. The present invention concerns the identification of new, potent and specific PARP inhibitors, based on the innovative and versatile chemical scaffold triazolobenzothiazole (TBT). They can be used a) to develop new anticancers that enrich the precision medicines armamentarium, b) to treat other pathologies in which PARP enzymes are involved, and c) as precious tools to unveil the physiopathological roles of the less explored PARPs.
Patent Status
PENDING
Priority Number
20225073 FINLAND
Priority Date
28/01/2022
License
INTERNATIONAL
Market
Cancer and inflammatory diseases are among the leading causes of morbity and mortality in Western countries. The therapies weigh heavily on health services and are even not satisfying. New and personalised therapeutics are urgently needed. The present invention responds to this request by proposing small molecules which selectively inhibit some of the 17 PARP enzymes, different from those affected by the approved PARPs inhibitors, with the potential to exert antitumor effects by a different mechanism. The four approved PARP inhibitors are already considered first-line therapies for the treatment of various cancers, let to envisage an important market for these next generation of PARPs inhibitors.
Problem
Cancer is a complex pathology that can be caused by many factors (e.g. genetic predisposition, lifestyle, environmental factors, and viral infections) and about 100 different kind of tumours are known, belonging to six different main categories (carcinoma, sarcoma, myeloma, leukaemia, lymphoma, mixed type). More than 2.7 million new cases of cancer are diagnosed in Europe per year with one in four deaths that can be attributed to cancer. Thanks to the early diagnosis and increasingly personalised medicines, the 51% and 38% of the diagnosed tumours in women and men, respectively, are successfully treated, but unfortunately, the other still remain incurable. This is mainly because of the late diagnosis, lack of adequate therapies, aggressiveness and low compliance of some treatments which are responsible for heavy side effects.
In parallel, more than 5 million people are affected by chronic inflammatory diseases (e.g. rheumatoid arthritis, lupus, atopic dermatitis, and Crohn’s disease) progressively debilitating, undermining people’s quality of life and creating socio-economic burdens. Chronic inflammation can also be precursor of certain cancers. Broad immunosoppressive treatments are usually employed, but alternative/personalized approaches are highly required.
The lead compounds object of the patent inhibit selectively certain PARPs which have recently emerged as important players in cancer and inflammation, thus suggestion them as alternative therapeutic options.
Current Technology Limits
Cancer remains a major cause of death globally. The current treatments are still largely bankrupt, with the chemotherapy that has many adverse side effects because simply it targets all the fast-growing cells, and the newer treatments that require tumor profile. In addition, all the current therapeutic options suffer of resistance development.
The small molecules PARP inhibitors identified in the present invention, after the appropriate optimization, have high probability to enrich the armamentarium of anticancer and/or anti-inflammatory personalized medicines. The approved PARPs inhibitors, olaparib and congeners, have already revolutionized the treatment of cancers with BRCA1/2 mutations such as breast, ovarian, fallopian, prostate and peritoneal and their use is expanding also in other cancers (as testified by the many ongoing clinical trials alone or in combination). Of note, while the approved PARPs inhibitors work by inhibiting the poly-ADP-ribosylating PARP1 and 2, our compounds inhibit specifically some of the mono-ADP-ribosylating PARP subfamilies, for which a multitude of physio/pathological roles are emerging. Thus, these compounds are expected to expand the use of PARP inhibitors in cancer treatment.
Killer Application
Our Technology and Solution
The 17 PARP enzymes play essential roles in various cellular processes catalyzing mono- or poly-ADP-ribosylation of proteins. Four inhibitors of poly-ADP ribosylating PARPs are already in therapy as anticancers.
We have identified a new chemical structure, the triazolobenzothiazole (TBT) scaffold, that efficiently recognizes PARP enzymes by mimicking the natural substrate NAD+. Under appropriate functionalization, the TBT scaffold gave compounds that specifically inhibit mono-ADP-ribosylating enzymes with nanomolar potency. In particular, we have identified the most potent inhibitors reported to date for PARP10 (IC50 = 7.8 nM), PARP15 (IC50 = 56 nM), and PARP12 (IC50 = 160 nM). The TBT scaffold was also high versatile allowing to identify also a potent inhibitor of poly-ADP-ribosylating PARP2 (IC50 = 44 nM). Its high suitability is confirmed by the appropriate cell-permeability, absence of cytotoxicity, and favorable pharmacokinetic properties of the derived compounds. In summary, our compounds based on TBT scaffold are:
Advantages
Roadmap
The optimization of the lead compounds reported in the patent to a drug candidate requires major investments by a pharmaceutical company that should takes care of all stages up to clinical approval. At the moment, Ribon Therapeutics, Takeda Pharmaceuticals and AstraZeneca are the companies mainly involved in the development of PARPs inhibitors. For these companies, our compounds could represents really valid lead compounds, mainly due to the novelty of the scaffold and their high degree of specificity for the less explored PARPs. Within the drug development process (lead optimization, preclinical studies, and clinical trials), the lead optimization phase could be performed in joint collaboration between company and the inventors. In particular, the group of Perugia can be involved in the structural optimization (design, synthesis, and characterization of the analogues), while the group of Oulu will take care of the PARPs profiling and structure studies.
TRL
Team
