Biological characterization of a novel potential acid ceramidase inhibitor in acute myeloid leukemia cells

• Grant number: 23/13541-1
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: August 01, 2024
• End date: November 30, 2024
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Daniel Fábio Kawano
• Grantee: Giovana da Costa Venancio
• Supervisor: David Feith
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Virginia (UVa), United States
• Associated to the scholarship: 22/12326-7 - Synthesis of a potential inhibitor of acid ceramidases targeting the prostate cancer treatment, BP.IC

Abstract

Acute Myeloid Leukemia (AML) is a blood and bone marrow malignancy that causes the proliferation of abnormal blood cells known as blasts. AML has a poor prognosis, with a 5-year survival around 28% or lower for patients older than 64 years. AML is also an extremely heterogeneous disease and even the most frequently mutated gene, the FLT3, only accounts for 30% of the cases. Therefore, therapies focusing on genetic mutations will only benefit part of the patients while the older ones, which represent the majority of those affected by AML, typically cannot endure intensive chemotherapy. Considering the need for novel drugs to treat AML, we are interested in therapies that could restore the apoptotic process in cancer cells, then promoting the selective death of neoplasic cells without compromising the integrity of healthy cells. Since lipid metabolism is largely dysregulated in cancerous AML cells, inhibitors from enzymes such as the acid ceramidase would combat the prolongated survival of cancer cell through its upregulated activity. In this context, our group developed a potential acid ceramidase inhibitor based on the known inhibitors benzoxazolone and LCL 264 and introducing some structural features from the 5-±-reductase inhibitor finasteride. Therefore, this project aims the biological characterization of the developed inhibitor ACI1 regarding its inhibition potency and cytotoxicity, which will be conducted in collaboration with the Loughran Lab at the University of Virginia.