Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape

Abstract

Introduction Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors; unregulated activation of the PI3K/PTEN/Akt pathway is a prominent feature of many human cancers. Akt is considered an attractive target for cancer therapy by the inhibition of Akt alone or in combination with standard cancer chemotherapeutics. Both preclinical animal studies and clinical trials in humans have validated Akt as an important target of cancer drug discovery. Area covered A historical perspective of Akt inhibitors, including PI analogs, ATP-competitive and allosteric Akt inhibitors, along with other inhibitory mechanisms are reviewed in this paper with a focus on issued patents, patent applications and a summary of clinical trial updates since the last review in 2007. Expert opinion A vast diversity of inhibitors of Akt, both small molecule and biologic, have been developed in the past 5 years, with over a dozen in various phases of clinical development, and several displaying efficacy in humans. While it is not yet clear which mechanism of Akt inhibition will be optimal in humans, or which Akt isoforms to inhibit, or whether a small molecule or biologic agent will be best, data to all of these points will be available in the near future.

Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models

“…Akt is critically involved in multiple signaling cascades, controlling cell growth and proliferation, and its activation is a prominent feature of many human cancers. On the basis of the strong rationale for targeting Akt for cancer therapy, multiple attempts to identify Akt inhibitors with acceptable pharmaceutical properties have been pursued (17). However, despite the significant progress in identifying Akt small-molecule inhibitors, selectivity has been a key issue for many previously reported ATP-competitive Akt inhibitors (relative to the kinome, especially within the AGC kinase family), raising concerns on safety and unclear mechanisms of action of these drugs.…”

“…The 3 isoforms of Akt have both overlapping and distinct functions and expression profiles (16,17). Activation of all 3 Akt family members have been detected in a variety of human malignancies, and inducible short hairpin RNA (shRNA) knockdown studies suggest that inhibition of all 3 Akt isoforms is required for maximum efficacy in PTENdeficient cancer xenograft models (18).…”

Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers

“…Inhibitors targeting the PI3K-AKT pathway members, including AKT, are currently in various stages of development (36,37). Previous studies have shown that AKT allosteric inhibitors require an intact PH-KD interface, because such inhibitors preferentially bind the closed PH-in conformation (16,17,38).…”

“…Several ATP-competitive and allosteric smallmolecule inhibitors of AKT are in development and/or clinical trials (36,37). Previous studies have shown that allosteric AKT inhibitors require an intact PH-KD interface for their activity (17,(38)(39)(40).…”

Pyrrolopyrimidine: A Versatile Scaffold for Construction of Targeted Anti-cancer Agents

“…The most common approaches described to date have been through the development of compounds that are either ATP-competitive or that prevent the formation of the active enzyme. 103 A number of Akt inhibitors are currently being tested in clinical trials, including allosteric inhibitors of inactive Akt. [104][105][106] CCT128930 (Compound 30) is a potent ATPcompetitive AKT inhibitor discovered using fragment and structure-based approaches.…”