Pan-cancer analysis identifies buckwheat-derived compound as potential AKT1 drug-design candidate

“AKT1 is a serine-threonine protein-kinase involved in tumour cell proliferation, survival, metabolism, and therapeutic resistance via activation of the PI3K/AKT/mTOR pathway.”

BUFFALO, NY - October 14, 2026 – A new research paper was published in Volume 17 of Oncotarget on October 12, 2026, titled “Integrative pan-cancer analysis of AKT1 and structure-based drug design by buckwheat derived compounds.”

The study examined the role of AKT1 across 33 cancer types and identified fagopyrine, a naturally occurring compound found in buckwheat, as a potential starting point for developing new AKT1-targeting drugs. By combining large-scale cancer datasets with computational drug-design techniques, the researchers identified cancer-specific patterns of AKT1 expression and predicted that fagopyrine could bind strongly to the AKT1 protein. However, its ability to inhibit AKT1 or produce anticancer effects has not yet been experimentally demonstrated.

The research was led by first and corresponding author Ramjan Sheikh, affiliated with the Plasma Cell Research Center and the Hajee Mohammad Danesh Science and Technology University.

AKT1 is a protein kinase involved in regulating cell growth, survival, metabolism and resistance to treatment. It functions within the PI3K/AKT/mTOR signaling pathway, a major network that controls how cells respond to growth signals and changing metabolic conditions. When this pathway becomes abnormally activated, it can contribute to uncontrolled cell proliferation and cancer progression. Understanding how AKT1 behaves across different tumors may therefore help identify potential biomarkers and therapeutic targets.

The researchers analyzed data from The Cancer Genome Atlas (TCGA) covering 33 cancer types, integrating information from multiple databases on gene expression, genetic alterations, DNA methylation, patient survival, immune-cell infiltration and drug sensitivity. This approach allowed them to investigate both the shared functions of AKT1 and the differences in its biological significance across malignancies.

The analysis revealed substantial variation in AKT1 expression between cancer types. Increased expression was observed in several malignancies, including breast, stomach and endometrial cancers, while other tumor types showed different expression patterns. AKT1 was also widely expressed in normal tissues, reflecting its essential role in cellular functions beyond cancer. These findings suggest that its relevance as a cancer biomarker or treatment target depends strongly on the biological context.

Survival analyses identified cancer-specific associations between AKT1 expression and patient outcomes. Higher AKT1 expression was associated with poorer overall and disease-free survival in liver hepatocellular carcinoma, lung adenocarcinoma and breast cancer. In kidney renal clear cell carcinoma, however, the opposite pattern was observed. This variability indicates that AKT1 expression cannot be interpreted as a universal indicator of cancer prognosis.

The researchers also examined the genetic and epigenetic mechanisms associated with AKT1 dysregulation. Genomic profiling identified alterations involving functionally important regions of the AKT1 protein, including recurrent missense mutations. DNA methylation analysis revealed reduced AKT1 promoter methylation in several cancers, including breast, kidney, liver and lung malignancies. These findings suggest that both genetic and epigenetic changes may contribute to abnormal AKT1 regulation.

Additional analyses explored the relationship between AKT1 and the tumor microenvironment. Single-cell expression data showed that AKT1 was present not only in malignant cells but also in immune and stromal populations, including macrophages, fibroblasts and endothelial cells. Its expression was also associated with tumor mutational burden and microsatellite instability in a cancer-dependent manner. Although these associations may be relevant to tumor biology and treatment response, their clinical significance remains to be established.

To investigate possible therapeutic opportunities, the researchers examined naturally occurring compounds derived from buckwheat. An initial collection of 97 phytochemicals was refined to 52 candidates suitable for computational screening against the AKT1 protein. Molecular docking was used to predict how these compounds might fit within AKT1's binding region and estimate the strength of their interactions.

Among the screened compounds, fagopyrine showed the strongest predicted binding affinity, with a docking score of −15.45 kcal/mol. The computational analysis identified several hydrogen-bonding and hydrophobic interactions between fagopyrine and amino acid residues within the AKT1 binding pocket. Other compounds, including quercetin, keracyanin, castasterone and α-amyrin, also showed favorable predicted interactions, although their docking scores were less favorable than that of fagopyrine.

The researchers then performed molecular dynamics simulations to investigate whether the predicted AKT1–fagopyrine complex would remain stable over time. During the 100-nanosecond simulation, the complex maintained a relatively stable structure, supported by analyses of molecular movement, protein flexibility and hydrogen-bond interactions. These results strengthened the computational evidence that fagopyrine could interact with AKT1, although they do not establish actual binding affinity or inhibition in biological experiments.

Density functional theory (DFT) analysis provided further information about the compound's electronic properties. The researchers observed relatively small changes in fagopyrine's electronic structure during the simulation, alongside an increased energy gap between its highest occupied and lowest unoccupied molecular orbitals. These findings were interpreted as evidence of favorable electronic stability within the modeled protein–ligand complex.

Despite these computational results, important limitations emerged from the predicted pharmacological and safety profiles. Fagopyrine showed moderate predicted gastrointestinal absorption and several violations of commonly used drug-likeness criteria, including relatively high molecular weight and lipophilicity. Its known photosensitizing properties also raise safety concerns, while a computational toxicity assessment flagged potential carcinogenicity. These findings indicate that the natural compound would require substantial modification and safety evaluation before it could be considered for therapeutic development.

“However, some of the drug-likeness restrictions that were predicted and the reported phototoxicity of native fagopyrine suggest that it should be regarded as a promising lead scaffold instead of a clinically applicable drug candidate.”

The findings provide a potential starting point for structure-based drug development rather than evidence of an effective anticancer treatment. Chemical modifications of the fagopyrine structure could eventually help researchers improve its pharmacological properties, reduce potential toxicity and investigate whether related molecules can selectively inhibit AKT1.

The study also has important limitations. Its conclusions were based on publicly available cancer datasets and computational modeling, without direct biochemical assays or cancer cell-line experiments confirming AKT1 inhibition by fagopyrine. Molecular docking scores and simulation stability cannot establish therapeutic efficacy, and predicted drug absorption or toxicity cannot replace experimental safety assessments.

Future investigations will need to test whether fagopyrine or optimized derivatives directly bind to and inhibit AKT1, affect downstream PI3K/AKT/mTOR signaling, and alter cancer-cell proliferation or survival. Additional pharmacokinetic, toxicity and animal studies would be necessary before considering clinical development.

Overall, the study provides an integrated view of AKT1 across multiple cancer types and identifies fagopyrine as a computationally prioritized compound for further drug-design research. By combining pan-cancer molecular profiling with structure-based screening, the findings offer a framework for investigating new AKT1-targeting molecules while emphasizing the need for experimental validation before any therapeutic application.

DOI: https://doi.org/10.18632/oncotarget.28922

Correspondence to: Ramjan Sheikh - rsheikh1996@universepg.com (ORCID: orcid.org/0009-0007-8248-7869)

Abstract video: https://www.youtube.com/watch?v=XNoPbxo8YJQ

Keywords: cancer, AKT1, pan-cancer, buckwheat, fagopyrine, molecular docking

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