Al-Rawi - Heterocyclic compounds as DNA-PK, PI3K and PDE3 inhibitors for treatment of cancer
Our group is interested in the synthesis of novel heterocyclic compounds such as DNA-PK, PI3K and PDE3 inhibitors for more effective treatment of cancer. We also use molecular modeling to explain drug receptor interactions.
There is significant interest in combination or dual kinase inhibitors in cancer drug discovery. The potential is not only to use kinase inhibition as a useful anti-cancer element itself, but also to augment existing but limited modes of cancer therapy.
DNA-PK is a prominent target as a potential combination therapy with existing anti-cancer drugs, such as etoposide and doxorubicin. The concept of dual DNA-PK PI3K inhibitors has been established in work done previously at Kudos (a company that was bought by Astra Zeneca in 2006 for $210 million). We seek to develop compounds with a similar activity profile but improved therapeutic properties.
Design, synthesis and modelling of heterocyclic compounds as DNA-PK and PI3K inhibiters for cancer treatment
DNA-dependent protein kinase (DNA-PK) is a key enzyme in the process of DNA repair, one of the key limiting factors to effective chemotherapy, causing drug resistance in a range of cancers. DNA-PK is a prominent target as a potential combination therapy with existing anti-cancer drugs, such as etoposide and doxorubicin. DNA-PK is structurally homologous to another signalling enzyme PI3K kinase, which promotes cell survival and proliferation and is up-regulated in many cancers. Dual DNA-PK and PI3K inhibitors are a promising class of potential therapeutic. We aim to synthesize and evaluate a library of 8-aryl-2-morpholino-1,3-benzoxazines that show these activities.
Synthesis and docking of 7-substituted-8-aryl-2-morpholino-1,3-benzoxazine as a selective PDE3 inhibition
Cyclic nucleotides are second messengers that are essential in vision, muscle contraction, neurotransmission, exocytosis, cell growth and differentiation. These molecules are degraded by a family of enzymes known as phosphodiesterases (PDES), which serve a critical function by regulating the intracellular concentration of cyclic nucleotides. Cyclic nucleotides are intracellular second messengers that play a key role in many physiological processes. The levels of these nucleotides are tightly regulated at the point of synthesis by receptor-linked enzymes (such as adenylyl or guanylyl cyclase) and at the point of degradation by a family of enzymes known as PDES. Our research involves the synthesis and docking of 7-substituted-8-aryl-2-morpholino-1,3-benzoxazine with known PDE3A, IC50 values. QSAR will then be used to predict the most active PDE3A inhibitor.
Meet the team