What We Do
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.
PIM kinase in autoimmune and inflammation
PIM kinase plays a critical role not only in cancer but also in key autoimmune and inflammatory processes through regulation of T and B cell function. PIM kinases are involved in T-cell amplification and differentiation, promoting inflammatory TH1 and TH17 effector cells (which influence further inflammatory cytokine production – IL-6, IL-17, TNFα, IFNγ). PIM expression suppresses anti-inflammatory regulatory T cells (further regulating TGF-β cytokine).
Image by: Kylie Seidner
PIM kinase inhibition has been shown to modulate immune environment, skewing T-cell differentiation from inflammatory Th1 and Th17 and to anti-inflammatory Treg phenotype. Rebalancing the immune system is an area of considerable industry interest and is being evaluated in many disease settings including rheumatoid arthritis (RA), psoriatic arthritis, osteoarthritis, IBD, psoriasis, atopic dermatitis, Type 1 diabetes, hidradenitis suppurativa, systemic lupus erythematosus, lupus nephritis, multiple sclerosis and celiac disease.
Expression of PIM kinases is regulated by the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, a critical signal transduction pathway which is dysregulated in autoimmune and inflammatory disease. JAK kinase inhibitors have been successfully developed for indications such as rheumatoid arthritis, inflammatory bowel disease and psoriasis, but carry warnings due to potential severe side effects (Kagstrup and Liew et al, RMD Open, Feb 2022). Downstream cellular targeting of the JAK/STAT pathway via PIM kinase inhibition may reduce these side effects thus allowing for a safer therapeutic approach.
Lupus Nephritis - PIM kinase is elevated in PMBCs, podocytes and glomeruli of lupus nephritis (LN) patients. PIM kinase inhibition has been shown to be efficacious in models of LN. PIM kinase inhibition would offer a differentiated mechanism of action to treat LN versus current approaches.
Rheumatoid Arthritis - PIM (gene and protein) is upregulated in synovial CD4+ T cells of early rheumatoid arthritis (RA) patients. PIM is also upregulated in RA fibroblast like synoviocytes (FLS) - FLS produce matrix metalloproteinases (MMPs) which contribute to bone and cartilage destruction. PIM kinase inhibition has been shown to limit arthritis progression and cartilage destruction in collagen induced arthritis (CIA) mice and to significantly reduce the production of MMPs by FLS.
Inflection is developing IBL-101, a pan-PIM kinase inhibitor with activity on all three isoforms. It is 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).
IBL-101 has been shown to be orally available with good pharmaceutical properties and with activity in a number of preclinical models related to autoimmune/inflammatory disease and cancer. The IBL-100s program was licensed to Mysthera Therapeutics in 2023.