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Phase 1, Phase 1/Phase 2, N/A
PKC inhibitor
AEB071 is an orally bioavailable PKC inhibitor with activity for isoforms of PKC1. Areas of Research: Diffuse large B-cell lymphoma and Uveal Melanoma.

Compound DescriptionOral, PKC inhibitor active for isoforms of PKC1

Areas of ResearchDiffuse large B-cell lymphoma and Uveal Melanoma

Proposed Mechanism of ActionPKC is a mediator of B-cell receptor (BCR)-NF-kB activation as it phosphorylates CARD11 of the CARD11-Bcl10-MALT1 (CBM) signaling complex. The CBM complex then activates the I kappa B kinase (IKK) complex, leading to the translocation of NF-kB to the nucleus and expression of its target genes.2 Isoforms of PKC have been shown to play a role in cellular signaling, proliferation, differentiation, migration, and apoptosis.1

A characteristic of activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) pathogenesis is the constitutive activation of the NF-kB pathway, via the CBM signaling complex, which promotes cell proliferation and differentiation, and suppresses apoptosis.2

Two Gα proteins, GNAQ and GNA11, are constitutively activated by point mutations in the majority of blue nevi and melanomas of the uvea.3 The signaling pathways downstream of the GNAQ and GNA11 proteins in uveal melanoma are less well understood than those of BCR signaling.4

Key Preclinical DataConsistent with the position of PKC as being downstream of BCR/CD79 and upstream of CARD11, preclinical studies show that ABC-subtype DLBCL cell lines carrying a mutation in the CD79 A or CD79 B gene are selectively sensitive to AEB071, while those with mutations in CARD11 are relatively insensitive.2 These data are supported by in vivo data in a mouse xenograft model of CD79-mutated DLBCL, which is also sensitive to AEB071.2 In vivo, mutant GNAQ and GNA11 transform melanocytes and induce rapid tumor growth in mice when introduced into immortalized murine melanocytes.3,5 Uveal melanoma cell lines with these mutations are selectively sensitive to PKC inhibitors.3,5

Clinical StatusTwo phase I studies of AEB071 are underway. The first is in patients with CD79-mutant DLBCL and the second is in patients with metastatic uveal melanoma.6,7

MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.
AEB071 is an investigational compound. Efficacy and safety have not been established.
There is no guarantee AEB071 will become commercially available.
  1. Skvara H, Dawid M, Kleyn E, et al. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J Clin Invest. 2008;118:3151–3159.
  2. Naylor TL, Tang H, Ratsch BA, et al. Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas. Cancer Res. 2011;71:2643–2653.
  3. Bastian BC. Somatic genetic alterations in melanoma: Implications for diagnosis, classification, and therapy stratification. In: Proceedings from The Beatson International Cancer Center, Cancer Models and Novel Therapies, July 3–6, Glasgow, UK.
  4. Rozengurt E. Mitogenic signaling pathways induced by G protein-coupled receptors. J Cell Physiol. 2007;213(3):589–602.
  5. Bastian BC. Therapeutic targets in uveal melanoma. Presented at the 102nd Annual Meeting of the American Association for Cancer Research (AACR), April 2–6, 2011; Orlando, FL.
  6. National Institutes of Health (NIH). Updated September 26, 2013. Accessed January 16, 2014.
  7. National Institutes of Health (NIH). Updated September 26, 2013. Accessed January 16, 2014.
  8. National Institutes of Health (NIH). Updated December 10, 2013. Accessed January 14, 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.

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