Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Efficient hit to lead optimisation utilising a REFiL workflow (#112)

Beatrice Chiew 1 , Dan Zheng 1 , Menachem Gunzburg 1 , David Chalmers 1 , Martin Scanlon 1 , Bradley Doak 1 , Stephen Headey 1
  1. Monash University, Parkville, VIC, Australia

Fragment based drug design (FBDD) is a robust drug discovery method with the approvals of two anti-cancer agents Vemurafenib1 and Venetoclax2, and the progression of over thirty other candidates through clinical trials. The key benefit of FBDD is the ability to explore vast amounts of chemical space through small fragments. Unfortunately, when initially optimising low-affinity fragments structural information can be scarce. We present an efficient means to overcome this hurdle using a Rapid Expansion of Fragments into Leads (REFiL) workflow.

When progressing diverse analogue series, lengthy synthesis is often undertaken to obtain lead compounds. Off-rate Screening (ORS) via Surface Plasmon Resonance (SPR)3 is a means to efficiently test small-scale crude mixtures from parallel synthesis without the need for extensive purification. Its value lies in the ability to clearly distinguish slow dissociating components from a mixture. As part of a REFiL workflow, ORS by SPR allows for rapid screening of crude compounds, which saves time and resources in the pursuit of desirable leads.

Here, we present a REFiL workflow which highlights parallel small scale synthesis using typical medicinal chemistry reactions and chemoinformatically designed diverse purchasable analogues and reagents sets to establish SAR and efficiently explore chemical space around a vector. With a robust means to assess quality (LCMS) and evaluate compound binding (ORS by SPR); kinetic, affinity and selectivity information can be rapidly acquired.
We demonstrate the practical application of REFiL to overcome key difficulties in developing fragment hits.

  1. 1. Bollag, G.; et al. Nature 2010, 467, 596-599.
  2. 2. Deeks, E. D. Drugs 2016, 76, 979-987.
  3. 3. Murray, J. B. et al. Journal of Medicinal Chemistry 2014, 57, 2845-2850.