Description:
Project ID: D2022-16
Background
Many cancer treatments target cells and induce apoptosis, a cell death mechanism. Due to genetic instability, tumors become more heterogeneous leading to cells that avert molecular signatures that are targeted by the cancer drugs. Drug resistance remains a major impediment to the success of a cancer treatment. Combinatorial treatment approaches 3,4 are adopted to decrease the chances of drug resistance and increase the chances of tumor eradication. However, differences in biodistribution can hinder the successful administration of drug combinations. Thus, combinatorial therapy works best when drugs demonstrate similar pharmacokinetic profiles. An emerging alternative is the rational design of multi-targeted hybrid molecules which will ensure homogenous spatiotemporal biodistribution of the individual active entities. Hybrid molecules acting as dual-mechanism anticancer agents are being developed to overcome the limitations of combination therapy.
Invention Description
Researchers at the University of Toledo have developed a new class of dual mechanism ferroptosis-HDAC inhibitor hybrids. They incorporate the pharmacophores of a ferroptosis inducer and a histone deacetylase (HDAC) inhibitor. Ferroptosis is a recently discovered nonapoptotic cell death mechanism characterized by a rapid increase in ROS leading to membrane lipid peroxidation. HDACs act as epigenetic regulators by inhibiting histone deacetylases. We combined the pharmacophores of SAHA and CETZOLE molecules to design the first-in-class dual mechanism hybrid molecules which induce ferroptosis and inhibit HDAC proteins. Analogue HY-1 demonstrated the best cytotoxic profile with GI50 values as low as 20 nM. cytotoxic effects were evaluated in a series of cancer and neuronal cell lines
Applications
-Hybrid has the potential to extend application to solid tumors
-Have the potential to prevent drug resistance and cancer metastasis
Advantages
-Economical and scalable method of synthesis
-kill cancer cells by a dual mechanism of action
-More active than SAHA (Vorinostat)
Publication
First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids. Manuscript under review. 2022