Leukemia is a group of blood cancers, such as acute leukemia, as we mentioned in our previous blog “BSc5371, an Irreversible FLT3 Inhibitor for Acute Leukemia Treatment”. Multiple myeloma is a cancer of plasma cells, called plasma cell myeloma. Such diseases severely affect patients’ lives. What is worse, they happen more frequently than before.
Several decades ago, people discovered the PIM gene. It is a recurrent proviral integration locus in Moloney murine leukemia virus. The overexpression of Pim kinases occurs when viral inserts at this site. There are 3 types in Pim kinase, including Pim-1, Pim-2, and Pim-3. They are sequence related constitutively active serine/threonine kinases. In some solid tumors, Pim kinases are always dysregulated or overexpressed. Thus, Pim kinases inhibition may be a potential way in multiple myeloma or leukemia research.
In recent study, Xiaojing Wang, et al identified a promising compound, GNE-955. In kinases assay, GNE-955 only inhibits 3 of 70 kinases by more than 80% at 0.1 μM. GNE-955 is a pan-pim inhibitor, with high affinity with Pim1, Pim2 and Pim3.
Additionally, GNE-955 exhibits profound activity in cellular assays. It inhibits the proliferation of MM.1S cells, with an IC50 value of 0.5 μM. GNE-955 suppresses the phosphorylation of BAD (s112), S6 (s235/236), S6 (s240/244) and 4EBP (s65) instead of total BAD, S6 and 4EBP protein levels. The concentration is in the range from 0.156 μM to 5 μM.
GNE-955 exhibits excellent not only in vitro activity, but also in vivo activity. It is orally active in rats, has good pharmacokinetic activity.
References:
1. Wang X, et al. J Med Chem. 2017 May 25;60(10):4458-4473.