# Advances in the Understanding of Akt Signaling in Cancers and the Potential of Inhibiting Akt-Driven Tumors Using Small Molecule Inhibitors: An Overview

## TL;DR

This review explores how natural products, especially from microbes, could offer better ways to target the Akt pathway in cancer, which is important for cell survival and growth.

## Contribution

The paper highlights novel microbial-derived compounds as selective Akt inhibitors with potential for improved cancer therapies.

## Key findings

- Microbial-derived compounds show promise in modulating PI3K/Akt signaling and suppressing cancer hallmarks.
- Current Akt inhibitors face challenges in isoform specificity and toxicity, prompting exploration of natural sources.
- Compounds like Bostrycin and Thiocoraline demonstrate anti-cancer effects in preclinical models.

## Abstract

The PI3K/Akt pathway is a key regulator of cancer cell survival and proliferation, but current inhibitors show limited clinical success due to poor isoform specificity and toxicity. These limitations have fueled growing interest in discovering Akt-selective inhibitors derived from natural sources, such as plants, animals and microbes. Notably, microbial-derived natural products have emerged as promising Akt-selective inhibitors, demonstrating suppression of major cancer hallmarks in preclinical studies. Collectively, this review highlights the oncogenic potential of Akt, its structure and regulation, isoform-specific functions, the critical role of mutations and posttranslational modifications, a summary of the small molecular inhibitors of Akt from plants, animals and microbes and their mechanisms, and discusses challenges and future directions for developing selective anticancer therapies.

The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is a central regulator of cellular metabolism, survival, and proliferation and is frequently dysregulated in cancer. Since the identification of protein kinase B (Akt) in 1996, extensive research has established its critical role in tumor initiation, progression, and therapeutic resistance, making Akt an attractive target for anticancer drug development. Although numerous inhibitors targeting the PI3K/Akt pathway have been developed, their clinical success has been limited due to inadequate isoform specificity and unfavorable toxicity profiles. These limitations have prompted increasing interest in identifying Akt-selective inhibitors from natural sources, particularly microbial metabolites. Recent in vitro and in vivo studies demonstrate that several microbial-derived compounds effectively modulate PI3K/Akt signaling and suppress key cancer hallmarks, including proliferation, angiogenesis, and metastatic potential. Nevertheless, further studies are required to define Akt isoform specificity, evaluate selectivity against closely related kinases, and validate therapeutic efficacy in relevant preclinical models, including patient-derived xenografts. In addition, the development of robust purification and optimization strategies remains essential to enable the reliable isolation and translational advancement of these bioactive metabolites. This review summarizes Akt structure, function, and key regulatory motifs relevant to pharmacological targeting and critically examines microbial-derived inhibitors of the PI3K/Akt pathway and their mechanisms of action. Representative compounds discussed include Bostrycin, Anthracycline analogs, Wentilactone A, Thiocoraline, Iturin A, SZ-685C, Isebromoamide B, Xyloketal B, and Demethoxyfumitremorgin C. Collectively, this review highlights the therapeutic potential of microbial natural products while outlining current challenges and future directions for developing selective Akt-targeted anticancer therapies.