(1239-D) Biophysics in Kinase Drug Discovery: from Fragment-based Screening to PROTAC Ternary Complex Characterization
Tuesday, February 6, 2024
2:00 PM – 3:00 PM EST
Location: Exhibit Halls AB
Abstract: PIM3 kinase, which belongs to the Ca2+/calmodulin-dependent protein kinase (CaMK) group, exhibits serine/threonine kinase activity. Similar to the other members of the PIM family (i.e. PIM1 and PIM2), PIM3 can prevent apoptosis, promote cell survival and protein translation. In addition, identifying potent and selective hits for PIM3 is of particular interest for the treatment of cancer. We designed a fragment-based screening cascade where biophysics was used for primary screening (MST/Spectral Shift). Then, we used other technologies, such as SPR and TSA, to perform orthogonal assays. The combination of these biophysical assays enabled us to identify fragments with affinity in the micromolar range, stabilizing properties and different binding sites. In parallel to our hit-finding activities, we used a AZD1208 scaffold as a starting point to generate PIM3 bifunctional protein degraders, and designed a specific screening cascade with biophysical assays included to characterize binary and ternary complex formation before in vivo studies.