Conception, synthesis and targeting of biomolecules - Institut Curie / CNRS UMR 176

Unit Director: Jean-Claude Florent
Deputy Director: Marie-Paule Teulade-Fichou

Keywords: medicinal chemistry, small molecule ligands, bioactive compounds, chemical library, compound libraries, anticancer therapeutics

The medicinal chemistry unit of the Institut Curie comprises two groups located on two sites: the Trouillet Rossignol Pavillon in central Paris and the Raymond Latarget Laboratory at Orsay. With shared supervision of CNRS, it includes about 15 permanent staff members and nearly as many postdocs, PhD, Masters and undergraduate students.

The central activity of our unit is to develop and use small molecule ligands to control the biological activities of important target proteins. We are using organic synthesis to construct new bioactive compounds, as well as natural-product analogues, new chemicals to cross-link proteins and new probes of biological function.

An important part of our work uses the Institut Curie–CNRS's proprietary library of 9 000 small chemical compounds packaged in 96-well plates (the ‘Chimiotheque' or Chemical library). ‘Hit' compounds are selected from this library by screening against a defined biological target. From these hit compounds, we can then design and synthesise analogues with improved selectivity or with other valuable properties. We are currently using a robot for the parallel synthesis of small libraries of compounds (in order) to turn the hits into lead compounds (improve the hits so that they become lead compounds).

Our research mainly covers compounds that might be useful for anticancer therapy:

• Antivascular compounds (such as tubulin-binding ligands).
• Inhibitors of serine/threonine protein kinases (CK2 and PIM-1), cyclin-dependent kinases, and the c-Kit receptor tyrosine kinase.
• Inhibitors of protein–protein interactions (for example, the interaction between the DNA polymerase delta subunit p66 and PCNA, a partner of DNA polymerases) and antagonists of the SH2 domains of GrB2, which are involved in its binding to phosphotyrosyl residues in growth factor receptors.
• DNA triple helix and G-quartet stabilisers, and telomerase and topoisomerase-2 inhibitors.
• Photodynamic therapy of tumors with new porphyrines.
• Antitumour drug-targeting compounds for antibody-directed enzyme prodrug therapy and glucuronide prodrug-based monotherapy (PMT).
• The Shigella bacterium's toxin, Shiga, conjugated to small molecules, small interfering RNAs or immunogenic peptides. (Shiga toxin is a natural ligand of a glycolipid expressed at high levels on some tumours.)

Group(s):

• Heterocyclic Chemistry, molecule interactions inhibitors
  Group leader: Marie-Paule Teulade-Fichou
• Medicinal Chemistry, Biorganic Chemistry, Drug Targeting
  Group leader: Jean-Claude Florent
• Organometallic chemistry, heterocycles and biological targets
  Group leader: Philippe Belmont