PIM proteins belong to a family of serine/threonine kinases composed of 3 isoforms, PIM1, PIM2 and PIM3, with greatly overlapping functions. Pim kinases play a key role in the cell cycle regulation, having potent anti-apoptotic activity.They also play a role in the homing and migration of metastatic cells.
Increased PIM kinase expression is associated with malignant subtypes of leukemia, lymphoma and a number of sold tumours including pancreatic, colorectal and oesophageal cancers.
PIM kinases share many of the same substrates as kinases of the Akt pathway. Thus, a PIM kinase inhibitor is well positioned for combination therapy with inhibitors of the Akt pathway (i.e., inhibitors of EGFR, PI3K, Akt and mTOR) and the mechanism is represented in the figure below.
Further third party research also has also shown that PIM kinase synergises with several other cell signalling pathways, providing a rationale to co-target such pathways with PIM kinase inhibiton, eg, JAK, MET, PD-1, BTK, BCL-2 and MYC.
Inflection is developing unique pan-PIM kinase inhibitors (IBL-100 series) with activity on all three isoforms. The molecules are highly selective for all three PIM isoforms in the low nanomolar to sub-nanomolar range and with no significant activities detected at sub-micromolar concentrations over 400 kinases on a kinome-wide scan. No cardiovascular concerns were found at therapeutic concentrations (in both HERG binding assay and functional patch-clamp electrophysiological assays).
The molecules have been shown to be highly orally available with excellent pharmaceutical properties and have shown activity in a number of preclinical models related to AML and non-small cell lung carcinoma.