Design of novel inhibitors of the FABP12 protein for drug development against advanced prostate cancer

Prostate cancer (PCa) is the second most common type of cancer worldwide, and the fifth leading cause of cancer death. New detection strategies have increased incidence rates in the last twenty years, and innovative therapeutic and risk-assessed strategies have drastically improved the 5-year survival expectancy of patients. Advanced prostate cancer, however, caused by the metastasization of aberrant cancer cells, is invariably fatal. This is thanks to the adaptive survival strategies of the tumor itself, which can become resistant to standard androgen-deprivation techniques and chemotherapeutic drugs. Prostate cancer undergoes two radical changes before becoming metastatic: one is the Epithelial-to-Mesenchymal Transition (EMT), which is the main hallmark of the start of the invasion of distant tissues and organs; the other is a change in the metabolism of the cancer cells themselves, which start relying on the beta oxidation of fatty acids instead of consumption of glucose for their metabolic needs. These two events are intricately tied together and are correlated to aberrant expression of Fatty Acid Transport Proteins (FABPs) in the surrounding tissues. FABPs are integral to the transport of fatty acids and other lipophilic substances into the cell membrane, and as such represent a source of energy for lipid metabolism of all types of cells in the body. FABP12, the most recently discovered member of the FABP protein family, plays a part in the metabolism of prostate cells, among other FABPs, but has been under the spotlight as the possible main drive behind aberrant metabolism and EMT in advanced prostate cancer. While potential inhibitors are known for the other FABPs, none of them, except for one, have been tested in-vitro for FABP12 inhibition. On top of that, no known FABP inhibitor has passed clinical trials for commercial drug usage. Finding potential inhibitors of FABP12 could be of great use in the research for therapeutic strategies against advanced prostate cancer: if the aberrant FABP12 expression is regulated by chemical compounds, then the uncontrolled expansion of the prostatic tumor could be slowed down. The research conducted in this thesis analyzes currently known inhibitors for all FABPs and uses in-silico computational methods to evaluate whether any of these could be a potential FABP12 inhibitor, thanks to molecular docking. Out of 816 investigated compounds, 13 of these are commercially available and possess a binding affinity for FABP12 higher than chemical compound BMS309403, a pan-inhibitor of the FABP protein family, which has historically been used as a comparative metric for both in-vitro and in-silico experiments. The compounds are also analyzed under the lens of ADMET properties, which highlight whether they have potential use as commercial drugs.