CX-6258 [(E)-5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one]
is an oral, small molecule inhibitor from a novel class of oxindole-based
derivatives that selectively inhibit all three Pim (Provirus Integration site for Moloney murine leukemia virus) kinases and show robust in vivo anticancer activity in Pim
kinase related xenograft models [1]. The pan-PIM inhibitory activity of CX-6258
(IC50 PIM-1, -2, -3 = 5, 25, 16 nM, respectively) is further strengthen
with a good inhibition values for Flt3 kinase (IC50 = 0.134 uM). Since
Flt-3 regulates the Pim kinases in leukemia, its level of inhibition is
important information for the interpretation of cellular activity performed
with Pim kinases inhibitors. CX-6258 was also shown to be a
reversible inhibitor of Pim-1 (Ki=0.005 uM).
Cylene Pharma disclosed CX-6258 in 2011, when
it was one the few pan-PIM kinase inhibitors. It was the first one with
nanomolar inhibition against Pim-3 kinase. With Pim-3 isoform reported to be overexpressed
in pancreatic, gastric, and colon cancer, CX-6258 could be beneficial as an
anticancer agent against these malignancies.
The activity of CX-6258 is as follows:
IC50 (Pim-1 enzyme assay) = 5 nM;
IC50 (Pim-2 enzyme assay) = 25 nM
IC50 (Pim-3 enzyme assay) = 16 nM
Common Name: CX-6258
Synonyms: CX-6258;
CX 6258; CX6258
IUPAC Name: (E)-5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one
CAS Number: 1202916-90-2;
1353858-99-7 (hydrochloride hydrate)
SMILES: CN1CCCN(C(C2=CC(C3=CC=C(/C=C4C(C=C(Cl)C=C5)=C5NC\4=O)O3)=CC=C2)=O)CC1
Mechanism of Action: Kinase
Inhibitor; pan-PIM Kinase Inhibitor
Indication: Various
Cancers
Development Stage: Pre-Clinical
Company: Cylene
Pharma
References:
1. Haddach, M.; et. al. Discovery of CX-6258. A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor. ACS Med Chem Lett 2011, 3(2), 135-139.
Pim kinases (Provirus Integration
site for Moloney murine leukemia virus) are a family of serine/threonine kinases
that regulate cell survival. This family of kinases is composed of three
different isoforms (Pim-1, Pim-2, and Pim-3) that share 60-70% sequence
identity in their kinase domains. The Pim kinases are tightly regulated at the
level of transcription and translation,5 and their expression is mediated by
the JAK/STAT signaling pathway, which is activated by various cytokines and
hormones. In addition, several oncogenes, including Flt3-ITD and Bcr/Abl, were
shown to upregulate the expression of Pims. The Pim kinase family members are
considered oncogenes and have been implicated in tumorigenesis either alone or
operating synergistically with c-Myc. Pim kinases are known to suppress
apoptosis by the direct phosphorylation and inhibition of pro-apoptotic Bcl-2
antagonist of cell death (BAD). Overexpression of Pim kinases has been reported
in leukemia and lymphoma tumors. They were also found to be overexpressed in
solid tumors, including pancreatic cancer and prostate cancer.
To assess its
selectivity profile, CX-6258 was
screened against 107 kinases where using a concentration of 0.5 µM, only Pim-1,
Pim-2, Pim-3, and Flt-3 were inhibited by more than 80%. The
antiproliferative activity of CX-6258 was
examined against a panel of cell lines derived from human solid tumors and
hematological malignancies. CX-6258 demonstrated
robust antiproliferative potencies against all cell lines tested. Cell lines
derived from acute leukemias were the most sensitive to CX-6258.
In mechanistic
cellular assays with MV-4-11 human AML cells, CX-6258 caused dose dependent inhibition of the
phosphorylation of two pro-survival proteins, Bad and 4E-BP1, at the Pim kinase
specific sites S112 and S65 and T37/46, respectively. Using ELISA against
phospho-Flt3 (Y591), researchers demonstrated that CX-6258 does not inhibit Flt3 activity in MV-4-11 cells at
relevant concentrations (IC50 greater than 10 µM) indicating that the effect of CX-6258
on phosphorylation of Bad and 4E-BP1 results
from direct inhibition of Pim kinases rather than being a secondary consequence
of Flt3 inhibition.
Combinations of CX-6258
with doxorubicin (10:1 molar ratio) and CX-6258
with paclitaxel (100:1 molar ratio) produced
synergistic PC3 cell killing with combination index (CI50) values
equal to 0.4 and 0.56, respectively. When used as single agent, the IC50
values for PC3 inhibiton were 13, doxorubicin, and paclitaxel 452 nM, 114 nM,
and 2.5 nM, respectively, supporting the role of Pim kinases in modulating the
chemosensitivity of cancer cells.
References:
1. Haddach, M.; et. al. Discovery of CX-6258. A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor. ACS Med Chem Lett 2011, 3(2), 135-139.
