Enzastaurin (DB06486): A Comprehensive Pharmacological and Clinical Review of a Revitalized Kinase Inhibitor

1.0 Executive Summary

Enzastaurin is an orally available, investigational small-molecule drug, chemically classified as a synthetic bisindolylmaleimide, that functions as a serine/threonine kinase inhibitor. Originally developed by Eli Lilly and Company, its primary mechanism of action involves the potent and selective inhibition of Protein Kinase C beta (PKCβ), with secondary activity suppressing the critical PI3K/AKT cell survival pathway. This dual inhibition results in multifaceted antitumor effects, including the induction of apoptosis, suppression of cellular proliferation, and inhibition of tumor-induced angiogenesis.

The clinical development of Enzastaurin has followed a remarkable and instructive trajectory. Despite promising preclinical data, the drug's initial path was marked by a significant setback in 2013 with the failure of the pivotal Phase III PRELUDE trial, which found no benefit for Enzastaurin as a maintenance therapy in high-risk diffuse large B-cell lymphoma (DLBCL). This outcome led to the cessation of its development by the originator.

The program was revitalized when Denovo Biopharma acquired the global rights and applied a precision medicine strategy. Through retrospective genomic analysis of samples from the PRELUDE and other trials, a novel predictive biomarker, Denovo Genomic Marker 1 (DGM1), was identified. This biomarker stratified a subpopulation of patients who demonstrated a significant survival benefit from Enzastaurin treatment. This discovery prompted a second wave of development, culminating in two new biomarker-guided, global Phase III trials: the ENGINE study in first-line high-risk DLBCL and the ENGAGE study in newly diagnosed glioblastoma (GBM).