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
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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