Glioblastomas (GBM) are the most common malignant brain tumors and are characterized by an aggressive invasive behavior associated with high drug resistance. Temozolomide is the only chemotherapeutic showing positive outcomes, but its efficacy is transient and occurs in a subgroup of patients. Thus, the clinical need is to
develop new specific anticancer agents targeting regulatory pathways outside the traditional chemotherapies.
Dopamine and its receptors are involved in the growth of cancers and, in particular, D4 receptor subtype (D4R) has recently been suggested as a potentially therapeutic target for the treatment of GBM. Metal-based drugs have also demonstrated to affect the spread and growth of different tumors, including GBM. The aim of this project is to
discover highly selective D4R antagonists as an innovative targeted therapy for GBM. These compounds will be structurally related to the M1 muscarinic agonist 77-LH-28-1, that has recently demonstrated to be also a potent and subtype selective D4R antagonist. Interestingly, 77-LH-28-1 bears an aliphatic butyl terminal, that makes it different from the D4R agents reported so far. Some of the ligands will be designed to coordinate metals, forming stable complexes that will act as antitumor agents through synergistic mechanisms of action, enhancing the dose delivered to the cancer cells. The most potent and selective D4R antagonists and relative complexes will also be
evaluated for their pharmacokinetic (PK) properties. The most interesting chemical entities will be used to investigate autophagy, mitophagy, apoptosis, paraptosis, senescence and invasion ability in GBM cell lines and stem cells. Moreover, to better elucidate the signaling pathways influenced by the D4R antagonist treatment,
protein arrays related to the most relevant kinases and stem markers will be performed. The new agents emerged from this project might become a new pharmacological approach in the treatment of GBM.