Identification of a new inhibitor of KRAS‐PDEδ interaction targeting KRAS mutant nonsmall cell lung cancer
Abstract
Oncogenic KRAS is considered a promising target for anti‐cancer therapy. However, direct pharmacological strategies targeting KRAS‐driven cancers remained unavailable. The prenyl‐binding protein PDEδ, a transporter of KRAS, has been identified as a potential target for pharmacological inhibitor by selectively binding to its prenyl‐binding pocket, impairing oncogenic KRAS signaling pathway. Here, we discovered a novel PDEδ inhibitor (E)‐N′‐((3‐(tert‐butyl)‐2‐hydroxy‐6,7,8,9‐tetrahydrodibenzo[b,dfuran‐1‐yl)methylene)‐2,4‐dihydroxybenzohydrazide(NHTD) by using a high‐throughput docking‐based virtual screening approach. In vitro and in vivo studies demonstrated that NHTD suppressed proliferation, induced apoptosis and inhibited oncogenic K‐RAS signaling pathways by disrupting KRAS‐PDEδ interaction in nonsmall cell lung cancer (NSCLC) harboring KRAS mutations. NHTD redistributed the localization of KRAS to endomembranes by targeting the prenyl‐binding pocket of PDEδ and exhibited the suppression of abnormal KRAS function. Importantly, NHTD prevented tumor growth in xenograft and KRAS mutant mouse model, which presents an effective strategy targeting KRAS‐driven cancer.
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NHTD redistributes the localization of KRAS to the endometrium through PDEδ-targeting isoprene binding pockets, and studies in vitro and in vivo have shown that NHTD can induce apoptosis and inhibit carcinogenic KRAS signaling by disrupting KRAS-PDEδ interactions (IC50 = 40 μM) in NSCLC, effectively preventing tumor growth in xenografted and KRAS-mutated mouse models.
“NHTD, on the other hand, redistributes the localization of KRAS to the endometrium through PDEδ-targeting isoprene binding pockets, and studies in vitro and in vivo have shown that NHTD can induce apoptosis and inhibit carcinogenic KRAS signaling by disrupting KRAS-PDEδ interactions (IC50 = 40 μM) in NSCLC, effectively preventing tumor growth in xenografted and KRAS-mutated mouse models.347”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [347]
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- Authors
- Leung, E. L., Luo, L. X., Li, Y., Liu, Z., Li, L. L., Shi, D. F., Xie, Y., Huang, M., Lu, L. L., Duan, F. G., Huang, J. M., Fan, X. X., Yuan, Z. W., Ding, J., Yao, X. J., Ward, D. C., & Liu, L.
- Affiliations
- Macau University of Science and Technology (MO)
- Guangzhou University of Chinese Medicine (CN)
- State Key Laboratory of Applied Organic Chemistry (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Yao, Xiao Jun
- Ward, David C.
- Liu, Liang
- ORCID
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2019-03-12
- Volume
- 145
- Issue
- 5
- Pages
- 1334-1345
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W2917582200
- Cited by
- 39
- References
- 37
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 7 · 2021: 9 · 2020: 1 · 2019: 2
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Lanzhou University Institutional Repository (submittedVersion)
- Funders
- Fundo para o Desenvolvimento das Ciências e da Tecnologia (010/2016/A1, 046/2016/A2, 086/2015/A3)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- KRAS, PDEδ, KRAS inhibitors, benzohydrazide, apoptosis, tumor growth inhibition, virtual screening
- MeSH terms
- A549 Cells, Animals, Benzofurans, Carcinoma, Non-Small-Cell Lung, Female, Humans, Hydrazones, Lung Neoplasms, Male, Mice, Nude, Random Allocation, Proto-Oncogene Proteins p21(ras), Rats, Sprague-Dawley, Xenograft Model Antitumor Assays, NIH 3T3 Cells, Cell Line, Tumor, Mice, Rats, Cyclic Nucleotide Phosphodiesterases, Type 6
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