Design and Synthesis of Bifunctional 3-D Building Blocks for Use in Medicinal Chemistry

This project is in collaboration with Professor Mike Waring (Newcastle University)

Background
Fragment-based methods are established for the identification of lead compounds in drug discovery.1 Fragments are small molecules (molecular weight ~150-300) which bind weakly to proteins. However, especially with X-ray crystal structures of protein-fragment complexes, the elaboration of a fragment to designed lead compounds (MW ~400-500) which are strong protein binders, can be achieved. The synthetic chemistry needed to optimise a fragment hit to a lead compound remains a bottleneck in fragment-based drug discovery, as highlighted by Astex recently.2 This is especially true when optimising along 3-D vectors. As a result, in this project, we will develop a modular synthetic platform that will enable fragments in current libraries (especially Waring’s FragLites3) to be elaborated into 3-D lead compounds with functionality in defined 3-D vectors.
Currently, there are no methods available for the modular, programmable elaboration of fragments to leads along 3-D vectors and the outputs from this project could provide a step-change in the way that this is carried out within the pharmaceutical industry. We will achieve this aim by the creation of a suite of bifunctional 3-D building blocks that will generate 3-D lead compounds by attaching the 3-D module to the fragment and to substituents to explore structure-activity relationships.

Objectives
1. Design and synthesis of 10 bifunctional 3-D building blocks
2. Development of synthetic chemistry for attachment of FragLites and further elaboration to lead-like compounds
3. Development of hit compounds against oncology protein targets

Experimental Approach
Initially, a set of 10 bifunctional 3-D building blocks will be designed to include common functionality for further elaboration. The 3-D building blocks will comprise a protected amine and a cross-coupling handle such as a vinyl or cyclopropyl boronate on different 3-D bicyclic, fused or spirocyclic scaffolds. The 3-D vectors provided by each novel, designed 3-D building block will be assessed using a computational tool to ensure that they provide distinct 3-D vectors compared to other building blocks. Then, each of the 3-D building blocks will be synthesised on a multi-gram scale, addressing issues of diastereo- and enantioselectivity. Next, it will be necessary to demonstrate that robust and orthogonal synthetic chemistry can be used to attached the 3-D building blocks to common fragments. For this, we will collaborate with Professor Waring (Newcastle University) and explore attachment of FragLites which have been recently developed in his group.3 It will also be necessary to explore methodology for further functionalisation of the FragLite-building block hybrid to explore lead-like space. Finally, through the collaboration with the Newcastle group, the elaboration of FragLite hits against oncology proteins to lead-like compounds will be also be explored.

Novelty
The concept of developing a synthetic platform to facilitate the elaboration of fragments to lead-like compounds is novel. It builds effectively on several hot topics in the synthesis and fragment medicinal chemistry arenas including the FragLite concept.

Training
This project will provide state-of-the-art training in modern synthetic methodology and medicinal chemistry. The graduating PhD student will be fully equipped for a future career in the pharmaceutical industry.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/.

You should expect hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject. Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/