Proviral integration site for Moloney murine leukemia virus kinase 1, 2, and 3 (PIM1, PIM2, PIM3)

Proviral integration site for Moloney murine leukemia virus kinases 1, 2, and 3 (PIM1, PIM2, PIM3) are a family of serine/threonine protein kinases with proto-oncogenic activity, constitutively active and lacking regulatory domains. Under physiological and pathological conditions, they are regulated by transcriptional activation (mostly downstream of JAK/STAT signaling) and post-translational degradation (e.g., ubiquitination), with major roles in cell growth, proliferation, survival, energy metabolism, cell cycle progression, angiogenesis, and resistance to apoptosis. They are overexpressed in numerous cancers and linked to therapeutic resistance, making them attractive drug targets for oncology. No PIM kinase inhibitors are currently approved for human use, but numerous preclinical candidates have shown efficacy in blocking cell proliferation and inducing apoptosis, especially in combination with other pathway inhibitors. Mechanistically, PIM kinases phosphorylate multiple substrates, including cell cycle regulators (p21, p27), apoptosis mediators (Bad), and oncoproteins (c-Myc), and can regulate mTOR signaling and cellular metabolism. Ongoing drug development includes ATP-competitive inhibitors and targeted protein degradation (PROTACs). Knockout studies indicate that inhibition is non-lethal, but optimizing therapeutic index and overcoming drug resistance remain key challenges.

Other names

PIM kinasesproto-oncogene proteins Pim-1Pim-2Pim-3PIM1 kinasePIM2 kinasePIM3 kinase

Inhibition of kinase activity (ATP pocket binding or allosteric inhibition); Induction of apoptosis by blocking PIM-mediated phosphorylation of pro-survival proteins; Synergistic downregulation of mTOR signaling (especially with agents like rapamycin); Proteolytic degradation of PIM kinases via PROTAC molecules