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LGH447
Phase 1
PIM inhibitor
Hemat
LGH447 is a selective, orally bioavailable, small molecule pan-PIM kinase inhibitor. Areas of Research: Hematologic malignancies and solid tumors.

Compound DescriptionOral, selective small molecule pan-PIM kinase inhibitor

Areas of ResearchHematologic malignancies and solid tumors

Proposed Mechanism of ActionThe PIM family consists of three serine/threonine protein kinases (PIM1–3) which play a role in cell cycle progression, cell survival, and tumorigenesis.1,2 Activation of c-Myc is commonly associated with PIM activation; the PIM family acts synergistically in carcinogenesis.1,3

In normal hematologic cells, PIM1 and PIM2 are expressed in response to multiple cytokines, chemokines and growth factors.2,4 Binding of these factors to their receptors leads to transcriptional activation of PIM genes via activation of the JAK/STAT signaling pathway.1

Elevated levels of PIM1 and PIM2 may be evident in patients with several hematologic malignancies.1,4 In addition, over-expression of PIM1 in prostate and pancreatic cancers, increased expression of PIM2 in liver cancer, as well as increased PIM3 in various solid tumors, have been reported.1,4

Inhibition of the pathway by LGH447 is through binding to all three PIM kinases.

Key Preclinical DataIn vitro studies in cell lines derived from a variety of hematological malignancies showed that LGH447 demonstrates anti-proliferative activity through inhibition of PIM kinases.5

LGH447 shows activity in vivo using hematological mouse xenograft models.6

Clinical StatusA phase I study using oral LGH447 in patients with multiple myeloma (MM) is under way.6

MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.
LGH447 is an investigational compound. Efficacy and safety have not been established.
There is no guarantee LGH447 will become commercially available.
References
  1. Nawijn MC, Alendar A, Berns A. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nat Rev Cancer. 2011;11:23–34.
  2. Aho TLT, Lund RJ, Ylikoski EK, et al. Expression of human pim family genes is selectively up-regulated by cytokines promoting T helper type 1, but not T helper type 2, cell differentiation. Immunology. 2005;116(1):82–88.
  3. van Lohuizen M, Verbeek, S, Krimpenfort P, et al. Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989;56:673–682.
  4. Brault L, Gasser C, Bracher F,et al. PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers. Haematologica. 2010;95:1004–1015.
  5. Novartis, data on file, 2013.
  6. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01456689. Updated October 7, 2013. Accessed January 13, 2014.

The information contained herein was last updated on April 12, 2013.

All Compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

The search results, details, and descriptions of clinical trials viewed in this app are supplied by ClinicalTrials.gov and EUtrialregistry.com. This information is maintained by a third party over whom Novartis Pharmaceuticals Corporation has no control. As such, Novartis Pharmaceuticals Corporation does not guarantee the accuracy, completeness, adequacy, or any other aspect of the information contained on this site.