PKC412--a protein kinase inhibitor with a broad therapeutic potential

The staurosporine derivative PKC412 was originally identified as an inhibitor of protein kinase C (PKC) and subsequently shown to inhibit other kinases including the kinase insert domain receptor (KDR) (vascular endothelial growth factor receptor, VEGF-R2), the receptor of platelet-derived growth factor, and the receptor for the stem cell factor, c-kit. PKC412 showed a broad antiproliferative activity against various tumor and normal cell lines in vitro, and was able to reverse the Pgp-mediated multidrug resistance of tumor cells in vitro. Exposure of cells to PKC412 resulted in a dose-dependent increase in the G2/M phase of the cell cycle concomitant with increased polyploidy, apoptosis and enhanced sensitivity to ionizing radiation. PKC412 displayed a potent antitumor activity as single agent and was able to potentiate the antitumor activity of some of the clinically used cytotoxins (Taxol and doxorubicin) in vivo. The combined treatment of PKC412 with loco-regional ionizing irradiation showed significant antitumor activity against tumors which are resistant to both ionizing radiation and chemotherapeutic agents (dysfunctional p53). The finding that PKC412 is an inhibitor of the VEGF-mediated cellular signaling via inhibition of KDR and PKC in vitro is consistent with the in vivo inhibition of VEGF-dependent angiogenesis in a growth factor implant model. Orally administered PKC412 also strongly inhibited retinal neovascularization as well as laser-induced choroidal neovascularization in murine models. In summary, PKC412 may suppress tumor growth by inhibiting tumor angiogenesis in addition to directly-inhibiting tumor cell proliferation via its effects on PKC and/or other protein kinases. PKC412 is currently in Phase I clinical trials for treatment of advanced cancer as well as for the treatment of ischemic retinopathy.