Luc Van Hijfte

Chief Scientific Officer, Drug Discovery, NovAliX, Building B: Structural Biology, BioParc, bld Sébastien Brant BP 30170, F-67405 ILLKIRCH Cedex, France

Abstract:

Screening of the anti-cancer kinase PIM1 using the Graffinity SPR screening technology on the NovAliB library allowed identifying mol to lowmdifferent fragment and lead-like motifs with activities in the low  mmol range, after confirmation of the hits using both a biochemical activity assay and noncovalent mass spectrometry. The more interesting fragments and lead-like molecules were soaked into in-house produced PIM1 crystals, and structural information on the binding mode was obtained from X-ray diffraction. The obtained information was used to design a new set of molecules, based on a rational fragment growing & merging approach. A first round of optimization led to double digit nanomolar active derivatives, and a second round of optimization led to the discovery of  SID222945 (MM 415 ; LE O.4), with a 9 nM activity on PIM1, and with an excellent selectivity for PIM1 & 3 over a set of 365 kinases as tested on the ProQinase platform.

This project clearly demonstrates the strength of the unique Graffinity SPR screening technology combined with the proprietary NovAliB chemical arrays, allowing to detect both fragments and related lead-like molecules in a high-throughput  fashion. The hits constitute excellent starting points for a fragment to lead process, by applying X-ray & MS biophysical techniques, to enable the fast generation (6 months) of high-quality lead molecules. Work is in progress to further fine-tune the newly discovered series with respect to the different activity, selectivity & ADMET properties, in a multifactorial & rational Design-Make-Test approach, to generate a high quality NME within the series.