Identification and Validation of Novel and Tractable PIM3 Starting Points and their Optimization
The PIM serine/threonine kinases (PIM1/PIM2/PIM3) are downstream effectors of ABL, JAK2 and Flt-3 oncogenes and are required for tumorigenesis. Overexpression has been reported in hematological and solid tumors, myeloma, lymphoma, leukemia, and adenocarcinoma. The first generation of PIM inhibitors to make it to the clinic, such as SGI-1776, AZD1208 and PIM447, are known to be pan-PIM inhibitors, while the aim of this project was to identify novel and selective PIM3 inhibitors. To this end, a range of complimentary approaches were employed including HTS, Fragment and Virtual Screening to rapidly generate novel chemical matter, which was assessed for its activity against PIM3 using a robust ADP-Glo™ assay.