Discovery of novel KRAS‒PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models
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KRAS‒PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36l (KD = 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS–PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft (PDX) models. It represents a promising lead compound for investigating the druggability of KRAS‒PDEδ interaction.
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Compound (131) is the most effective small molecule inhibitor of KRAS-PDEδ reported to date, suggesting its potential as a therapeutic agent for the treatment of pancreatic cancer.
“Additionally, it is the most effective small molecule inhibitor of KRAS-PDEδ reported to date, suggesting its potential as a therapeutic agent for the treatment of pancreatic cancer.355”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [355]
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References 45 · Cited by 20
- Authors
- Chen, L., Zhang, J., Wang, X., Li, Y., Zhou, L., Lu, X., Dong, G., & Sheng, C.
- Affiliations
- Second Military Medical University (CN)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Corresponding author
- Lu, Xiongxiong
- Dong, Guoqiang
- Sheng, Chunquan
- Venue
- Acta Pharmaceutica Sinica B
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 12
- Issue
- 1
- Pages
- 274-290
- ISSN
- 2211-3835 (ISSN-L)
- PMC
- PMC8799878
- OpenAlex
- W3184599439
- Cited by
- 20
- References
- 45
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 6 · 2023: 5
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (21738002, 81725020, 81903436, 82030105)
- National Key Research and Development Program of China (2020YFA0509100)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- 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
- Keywords
- pancreatic cancer, spiro compounds, mutant KRAS, patient-derived xenografts, ERK1/2 phosphorylation, Akt phosphorylation, apoptosis, MIA PaCa-2 cells, anticancer activity
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