Enzastaurin: A lesson in drug development.
Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. It was initially developed as an isozyme specific inhibitor of protein kinase Cβ (PKCβ), which is involved in both the AKT and MAPK signalling pathways that are active in many cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. In this review, we will discuss the development of enzastaurin from drug design to clinical testing, exploring target identification, validation and preclinical assessment. Finally, we will consider the clinical evaluation of enzastaurin as an example of the challenges associated with drug development. In particular, we discuss the poor translation of drug efficacy from preclinical animal models, inappropriate end point analysis, limited standards in phase I clinical trials, insufficient use of biomarker analysis and also patient stratification, all of which contributed to the failure to achieve approval of enzastaurin as an anticancer therapeutic.
Department of Biochemistry & Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Canada. Electronic address: Tarryn.bourhill@ucalgary.ca.
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Bourhill
Department of Biochemistry & Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Canada.
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Narendran
Department of Biochemistry & Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Canada.
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Johnston
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D007211:Indoles; D064546:Protein Kinase C beta; C504878:enzastaurin
Drug development; Enzastaurin; Protein kinase C