Session: Posters:

Pyrimethamine (PYM) is a poly-pharmacological small molecule that has been used as medication for toxoplamosis with target of Dihydrofolate Reductase (DHFR) inhibitor. It was considered as Anti-Malaria medication once and stopped due to resistance. Currently, it is studied in clinical trial to Chronic lymphocytic leukemia (CLL) as STAT3 inhibitor. Many cancers can be highly dependent on STAT3 pathway overregulation to maintain their proliferation and survival rate. Unfortunately, to date, there is still no STAT3 inhibitors passing Phase 2 clinic trials due to multiple reasons such as overtoxicity, off-targeting effects and lack of pharmacokinetics profiles. Through the unbiased docking study in previous study, we found two interesting binding pockets for Pyrimethamine and its Histone Deacetylase inhibitor (HDACi) analogue at DNA binding domain. According to the hydrophobicity, charges, and possible hydrogen bonding in the pockets, we have designed three classes of novel PYM analogues as STAT3 inhibitors. The selected Class II agents 11b-d showed a 100-fold enhancement of cytotoxicity and 100-fold improvement of STAT3 pathway inhibition comparing to PYM. More importantly, we found that this class showed STAT3 DNA binding interruption, which indicates the compounds interact with the expected binding pockets in DNA binding domain. Moreover, the selected candidate has a significant S phase arrest in cell cycle, which is similar to PYM. Here we conclude that the novel PYM derivatives can be a potential therapeutic strategy of STAT3 inhibition in cancer treatment.

Dr. Bocheng Wu

PhD student, Georgia Tech

Appearances