Enzastaurin.
OBJECTIVE
Enzastaurin - a novel oral antitumor agent that selectively inhibits protein kinase Cbeta activity - has demonstrated promise in phase I and II trials in various advanced cancers, and is being investigated in multiple hematologic malignancies and solid tumors.


RESULTS
Enzastaurin (LY317615) was initially developed as an antiangiogenic cancer therapy. Subsequent preclinical studies showed its antitumor effect by inhibiting tumor proliferation and inducing apoptosis on multiple cancer cell lines as well as xenograft models. Enzastaurin not only inhibits protein kinase Cbeta activity but also suppresses signaling through the phosphoinositide-3 kinase/AKT pathway. Based on the phase I study, 525 mg/day is the recommended dose for oral enzastaurin. It is well tolerated at this dose, with no clinically significant grade 3 or 4 toxicities. A recent phase II study of enzastaurin in patients with relapsed or refractory diffuse large B-cell lymphoma showed enzastaurin to be associated with prolonged freedom from progression. Several preliminary studies showed promising results in patients with various advanced cancers and suggested that enzastaurin can be safely used long term in combination with traditional chemotherapies.


CONCLUSIONS
Enzastaurin is emerging as a promising new antitumor treatment. This review addresses the mechanism of action, development, preclinical studies, and clinical study results with enzastaurin.
Ma
Shuo
S
Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA.
Rosen
Steven T
ST
D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002986:Clinical Trials as Topic; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D064546:Protein Kinase C beta; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C504878:enzastaurin