Menu
MapConnectionsTopicsBulgariaThe Night (K-TRIO)Marie Skłodowska-CurieFor studentsFor teachersMethodologySurprise me
H2020Individual fellowship2018–2020

SYNFOS · Synthetic toolkit for fragment oriented synthesis

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2018-03-01 → 2020-02-29
EU contribution
€195,455
Participants
1
Scheme
MSCA-IF

Lines connect the coordinator with its partners.

Results in brief

Synthetic toolkit for fragment oriented synthesis

The discovery of small bioactive molecules is a central challenge in chemical biology and medicinal chemistry, and typically involves iterative cycles of design, synthesis and biological evaluation. A narrow toolkit of reliable synthetic methods drives such workflows, and focuses on heteroatom / sp2 carbon functionalization and protecting group manipulation. The dominance of the toolkit has tended to exacerbate the historically uneven exploration of chemical space, and to focus attention on flatter and more lipophilic compounds. Within fragment-based drug discovery, direct fragment growth is rare, essentially being limited to heteroatom functionalization. In practice, more elaborated fragments tend to be synthesised de novo when direct fragment elaboration would actually be desirable. Direct fragment growth will not only contribute to improve productivity of early stages drug development by reducing the synthetic burden, but also will allow to navigate through unexplored chemical space. In particular, the exploitation of molecules with increased tridimensionality has been linked to the discovery of drug candidates with higher probabilities of reaching the market. Hence, the research proposed for the current action will contribute with know-how to the global efforts of targeting new diseases by providing new better drugs while increasing pipeline productivity. The overall objective of the action is the development of a synthetic toolbox that facilitates the introduction of a range of medicinally-relevant functionalities into fragment molecules through their direct activation. The toolbox usefulness will be demonstrated by the discovery of new bioactive molecules able to interact with protein function.

Data: CORDIS, © European Union

Project objective

Fragment-based ligand discovery (FBLD) has become a mainstream strategy to discover new drugs to enable the treatment of conditions with unmet medical needs. Despite the remarkable rise of FBLD, significant chemical challenges remain in the field; firstly, elaborated fragments tend to be synthesised de novo when direct growth would be much more advantageous. Secondly, the currently available toolkit for fragment elaboration tends to exacerbate an uneven exploration of chemical space, yielding flatter and more lipophilic compounds.SYNFOS will allow Alexandre Trindade (the fellow) to join the laboratory of Professors Adam Nelson (host supervisor) and Steve Marsden (host co-supervisor) at the University of Leeds (Host) and develop research expertise in fragment-based ligand discovery; catalysis to enable molecular discovery; protein-protein interaction (PPIs) inhibition; and high-throughput X-ray crystallography (via secondments to Diamond (Partner)). In doing so, the fellow will (a) enhance his prospects of becoming an independent academic group leader in Europe and (b) address the need to train researchers in key multidisciplinary areas such as medicinal chemistry and chemical biology and (c) develop cutting edge synthetic methods that facilitates the fragment-based discovery of new inhibitors for protein-protein interactions. By building in fragment hits from the Host laboratory, the fellow will establish a synthetic toolkit enabling the functionalization of C-H bonds within N-heterocycles with a wide range of medicinally-relevant groups. The fellowship will explore three main modes of reactivity to establish the functionalization of sp3-hydridised carbons with heterocyclic fragments and showcase the value of the synthetic toolbox through the discovery of fragments hits into potent inhibitors of PPIs involving the ATAD2 bromodomain.

Original text from CORDIS.

Participants

Links

Data: CORDIS, © European Union