Ly333531 104

very high binding to the a-acid glycoprotein component of human blood. Midostaurin (PKC-a IC50 = 3 nM) inhibits cancer cell growth at ~0.5 mM, and is active in animal models of metastatic melanoma when given at a dose of 75 mgkg _ 1 three times daily by the intraperitoneal route.454 It too is highly bound to a-acid glycoprotein, has a human half-life of 40 h, and has progressed to Phase II trials,455 principally in leukemias. The compound has demonstrated some antitumor effects, with side effects of nausea, diarrhea and neutropenia. Ro 31-8220 (103) has also entered clinical trials,446 although the true effect of PKC inhibition may be masked by the broad kinase inhibitory profile of the compound.

Bryostatin, a marine-derived natural product, inhibits PKC by interacting with the regulatory domain of the kinase,456 acting as an analog of diacylglycerol. It is unusual in that it initially activates PKC, which leads to a rapid downregulation of the enzyme. Phase II studies against a variety of tumor types gave no conclusive activity, but did result in some disease stabilization.457 Lipid analogs such as imofosine458 and perifosine,459 which also target the regulatory domain of PKC, have also progressed to the clinic for cancer treatment.

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