Pyrroloquinoline alkaloids from marine bacteria as irreversible kinase inhibitors

• Applicant: Dr. Daniela Reimer
• Subject Area: Biological and Biomimetic Chemistry ; Biochemistry ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2015 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271439282

Natural products are a dominant player in drug discovery and recent anticancer drug approvals highlight natural products from marine derived organisms as a promising source for new drug leads. Kinases as regulators of cellular signaling have become an important group as drug targets in the treatment of cancer. Irreversible protein kinase inhibitors bind in a covalent manner to a nucleophilic cysteine residue in the kinase active site located next to the ATP binding pocket. As the localization of these corresponding cysteine residues differs in different kinase inhibitor classes, covalent protein kinase inhibitors possess a high grade of selectivity and potency compared to other kinase classes. To avoid toxicity from nonspecific binding with other cysteine/ATP binding pockets from different protein classes, drug design of this compound class must take into account the exact degree of electrophilicity needed and the correct orientation of the structurally-important moiety to enable an optimal binding reaction. Pyrroloquinoline alkaloids from marine organisms such as lymphostin have been described as kinase inhibitors. Although, several targets of lymphostin, e.g., lymphocyte kinase Lck, phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) have been identified, the explicit mode of action as a kinase inhibitor is still unknown. As the human genome posses about 518 kinases and the development of lymphostin into a drug requires a high degree of kinase selectivity, a complete picture of kinase inhibition will provide important knowledge. Therefore, in this research project, different derivatives harboring structural moieties of lymphostin and the structural related ammosamides will be explored. Semi- and total synthesis of natural and unnatural compounds in combination with affinity and fluorescent probes will be used to identify potential protein targets. Kinase and cell-based bioassays will be used to evaluate the anticancer potential of these derivatives. Structure-activity relationship (SAR) and mode of action studies should support the hypothesis that these compounds act as electrophilic natural products. It is expected that the lymphostin natural product evolved to be an irreversible competitive inhibitor of ATP.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Connor Hughes Chambers, Ph.D.