PIM447
[N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide]
is a novel, specific pan-Pim kinase inhibitor in development for the treatment
of patients with multiple myeloma (MM) and other hematologic malignancies.
PIM447 demonstrated significant tumor growth inhibition in xenograft mouse
models of MM as compared with control animals, supporting the clinical
development of PIM447 in MM patients. PIM447 is currently in several phase 1
trials of cancer patients with hematological malignancies.
The biochemical potency for PIM447 was assessed in a high ATP AlphaScreen assay using [ATP]’s of 2800, 500, and 2800 µM for PIMs 1, 2, and 3, respectively. Under these conditions, the Ki ’s of PIM447 were determined to be 6, 18, and 9 pM for PIMs 1, 2, and 3, respectively [1]. The kinase selectivity of PIM447 was determined in biochemical assays for a panel of 68 diverse protein kinases includeding PIM2 as well as 9 lipid kinases. In this panel, only PIM2 was significantly inhibited by PIM447 with an IC50 of less than 0.00035 µM. PIM447 also inhibited GSK3ß (IC50 = 1.3 uM), PKN1 (IC50 = 4.9 uM), and PKCt (IC50 = 4.1 uM), but at a significantly lower potency with IC50.
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| PIM447: 2D and 3D Structure |
The biochemical potency for PIM447 was assessed in a high ATP AlphaScreen assay using [ATP]’s of 2800, 500, and 2800 µM for PIMs 1, 2, and 3, respectively. Under these conditions, the Ki ’s of PIM447 were determined to be 6, 18, and 9 pM for PIMs 1, 2, and 3, respectively [1]. The kinase selectivity of PIM447 was determined in biochemical assays for a panel of 68 diverse protein kinases includeding PIM2 as well as 9 lipid kinases. In this panel, only PIM2 was significantly inhibited by PIM447 with an IC50 of less than 0.00035 µM. PIM447 also inhibited GSK3ß (IC50 = 1.3 uM), PKN1 (IC50 = 4.9 uM), and PKCt (IC50 = 4.1 uM), but at a significantly lower potency with IC50.
Additional kinase profiling of PIM447 at 1 µM against 442 kinases using the
KINOMEscan binding displacement assay, indicated high kinase selectivity for
PIM1,2 and 3.
Novartis
is developing PIM447 (earlier named as LGH447), in relapsed, refractory MM, and
further suggest that it may be effective in the treatment of AML and other
hematological malignancies, either as a single agent or in combination with
other select therapeutic agents.
PIM447 Synthesis
PIM
Kinase
The PIM
(Provirus Integration site for Moloney leukemia) kinase gene family encodes 3
serine/threonine protein kinases (PIM-1,2,3) that have roles in cell cycle
progression and survival. In human disease, elevated levels of PIM1 and PIM2
are associated with hematologic malignancies, with MM showing the highest level
of PIM2 expression. In preclinical studies, a majority of MM cell lines proved
sensitive in vitro to LGH447-mediated PIM inhibition, exhibiting a
dose-dependent decrease in cell proliferation.
PIM1,
PIM2, and PIM3 are a closely related family of constitutively active
serine/threonine kinases. PIM kinases were first identified as common
integration sites in MMLV-induced murine T-cell lymphomas, with these viral
insertions resulting in transcriptional activation and expression of the
kinase. Similar unbiased insertional mutagenesis screens were used to
demonstrate that the three kinases could substitute for each other in this
oncogenic process, indicating that inhibition of all three PIM kinases may be
necessary to achieve a therapeutic benefit. In human cancers, increased
expression and activity of PIM kinases has been detected in many hematopoietic
malignancies and solid tumors (prostate, lung, liver) and it is thought that
this contributes to cancer cell survival and proliferation in these
malignancies.
Activity
of PIM447
PIM447 (also LGH447),
a potent and specific pan-PIM inhibitor is shown to be active in PIM2-dependent
Multiple Myeloma (MM) cell lines by inhibiting proliferation, mTOR-C1 signaling
and phosphorylation of BAD. In addition, LGH447 inhibited proliferation of
several AML cell lines. Furthermore, LGH447 inhibits tumor growth in several
mouse subcutaneous xenograft models of MM and AML, where modulation of the
pharmacodynamic marker phospho-S6 Ribosomal Protein was used to predict
efficacy. LGH447 significantly reduced the bone tumor burden in a disseminated
orthotopic human xenograft model of MM. Finally, researchers have demonstrated
increased activity of LGH447 in combination with the PI3K inhibitor BYL719 in a
MM model and with Cytarabine in an AML model.
Identifications:
Identifications:
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| 1H NMR (Estimated) for PIM447 |
References:
1. Burger,
M. T.; et. al. Identification of
N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide
(PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine
Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for
Hematological Malignancies. J Med Chem 2015, 58(21), 8373-8386.
2. Burger, M. T.; et. al. Kinase inhibitors and methods of their use. US9079889B2
2. Burger, M. T.; et. al. Kinase inhibitors and methods of their use. US9079889B2
