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- W2009185488 abstract "The Pim protein kinases, first identified as a proviral integration site in c‐Myc overexpressor mice, are increased in multiple human hematopoietic neoplasms including myeloid leukemia, diffuse large B‐cell lymphoma, and T‐cell lymphoma. We have developed novel benzylidene‐thiazolidine‐2, 4‐diones (J. Med. Chem. (2009) 52:74) inhibitors of Pim kinases that kill a wide range of both myeloid and lymphoid cell lines with precursor T‐cell lymphoblastic leukemia/lymphoma (pre T‐LBL/T‐ALL) being the most sensitive. The most potent members of this chemotype have IC50s of 13 nM for Pim‐1 and 2.3 M for Pim‐2 while some compounds in this chemotype demonstrated selectivity9s of more than 2500‐fold and 400‐fold for Pim‐1 or Pim‐2 respectively while other congeners had equivalent potency towards both isozymes. Of the 47 additional protein kinases tested, only DYRK1a was sensitive to these agents. Incubation of pre T‐LBL cells with one of these Pim inhibitors, SMI‐4a, induced G1 phase cell cycle arrest secondary to a dose dependent induction of p27Kip1 and translocation of this protein to the nucleus. Additionally, SMI‐4a induced apoptosis in these leukemic cells through the mitochondrial pathway, and inhibited mTORC1 pathway based on decreases in phosphorylation of p70 S6K and 4E‐BP1, two substrates of this enzyme. Using immuno‐deficient animals, we demonstrate that treatment 5/7 days with 60 mg/kg twice daily by oral gavage of SMI‐4a inhibits subcutaneous growth of pre T‐LBL tumors by an average of 47.9% (p Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B249." @default.
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- W2009185488 date "2009-12-10" @default.
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- W2009185488 title "Abstract B249: Small molecule inhibitors of the Pim protein kinases block the growth of T‐acute lymphoblastic leukemias" @default.
- W2009185488 doi "https://doi.org/10.1158/1535-7163.targ-09-b249" @default.
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