Friday, May 8, 2015

PIM447 | pan-PIM Kinase Inhibitor | LGH447

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.

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

US9079889B2: The patent reports many possible routes for the synthesis. The route appears to be an industrial one. Also see Ref. 1.

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.


1H NMR (Estimated) for PIM447

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