Discovery of Novel KRAS-PDEδ Inhibitors by Fragment-Based Drug Design

RAS oncogenes: the first 30 years

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Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

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Discovery of Small Molecules that Bind to K‐Ras and Inhibit Sos‐Mediated Activation

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The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins

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Ligand efficiency as a guide in fragment hit selection and optimization

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Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo

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KRas Localizes to the Plasma Membrane by Spatial Cycles of Solubilization, Trapping and Vesicular Transport

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Therapeutic intervention based on protein prenylation and associated modifications

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Identification of pyrazolopyridazinones as PDEδ inhibitors

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Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities

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Lipidated Ras and Rab Peptides and Proteins—Synthesis, Structure, and Function

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Photoreceptor cGMP Phosphodiesterase δ Subunit (PDEδ) Functions as a Prenyl-binding Protein

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The δ Subunit of Retinal Rod cGMP Phosphodiesterase Regulates the Membrane Association of Ras and Rap GTPases

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A PDE6δ‐KRas Inhibitor Chemotype with up to Seven H‐Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2

Martín‐Gago, P., Fansa, E. K., Klein, C. H., Murarka, S., Janning, P., Schürmann, M., Metz, M., Ismail, S., Schultz‐Fademrecht, C., Baumann, M., et al. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201610957 · Cited by 89 · see citing works

Fragment Informatics and Computational Fragment‐Based Drug Design: An Overview and Update

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Synthesis of the Rheb and K‐Ras4B GTPases

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Speeding up Early Drug Discovery in Antiviral Research: A Fragment-Based in Silico Approach for the Design of Virtual Anti-Hepatitis C Leads

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Structure Guided Design and Kinetic Analysis of Highly Potent Benzimidazole Inhibitors Targeting the PDEδ Prenyl Binding Site

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Fragment-based in silico modeling of multi-target inhibitors against breast cancer-related proteins

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De novo computational design of compounds virtually displaying potent antibacterial activity and desirable in vitro ADMET profiles

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Development of Pyridazinone Chemotypes Targeting the PDEδ Prenyl Binding Site

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Structural Biology-Inspired Discovery of Novel KRAS–PDEδ Inhibitors

Jiang, Y., Zhuang, C., Chen, L., Lu, J., Dong, G., Miao, Z., Zhang, W., Li, J., & Sheng, C. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01243 · Cited by 34 · see citing works

Ecotoxicity interspecies QAAR models from Daphnia toxicity of pharmaceuticals and personal care products

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Structure-based development of PDEδ inhibitors

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Phosphodiesterase 6 subunits are expressed and altered in idiopathic pulmonary fibrosis

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Multitasking Model for Computer-Aided Design and Virtual Screening of Compounds With High Anti-HIV Activity and Desirable ADMET Properties

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Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials

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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works

Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions

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Fragment-to-Lead Medicinal Chemistry Publications in 2018

Erlanson, D. A., de Esch, I. J. P., Jahnke, W., Johnson, C. N., & Mortenson, P. N. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01581 · Cited by 77 · see citing works

Selection of Nucleotide-Encoded Mass Libraries of Macrocyclic Peptides for Inaccessible Drug Targets

Colas, K., Bindl, D., & Suga, H. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00422 · Cited by 77 · see citing works

Discovery of Novel PDEδ Degraders for the Treatment of KRAS Mutant Colorectal Cancer

Cheng, J., Li, Y., Wang, X., Dong, G., & Sheng, C. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00929 · Cited by 67 · see citing works

Discovery of Novel PDEδ Autophagic Degraders: A Case Study of Autophagy-Tethering Compound (ATTEC)

Bao, J., Chen, Z., Li, Y., Chen, L., Wang, W., Sheng, C., & Dong, G. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.3c00161 · Cited by 35 · see citing works

Deubiquitinase inhibitor degrasyn suppresses metastasis by targeting USP5‐WT1‐E‐cadherin signalling pathway in pancreatic ductal adenocarcinoma

Li, J., Li, H., Zhu, W., Zhou, B., Ying, J., Wu, J., Zhang, H., Sun, H., & Gao, S. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14813 · Cited by 32 · see citing works

Target-Based Small Molecule Drug Discovery for Colorectal Cancer: A Review of Molecular Pathways and In Silico Studies

Moshawih, S., Fern, L. A., Ardianto, C., Goh, K. W., Kifli, N., Goh, H. P., Jarrar, Q., & Ming, L. C. (2022) · Biomolecules · doi:10.3390/biom12070878 · Cited by 31 · see citing works

Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction

Chen, D., Chen, Y., Lian, F., Chen, L., Li, Y., Cao, D., Wang, X., Chen, L., Li, J., Meng, T., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.12.018 · Cited by 31 · see citing works

An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth

Kaya, P., Schaffner‐Reckinger, E., Manoharan, G. B., Vukić, V., Kiriazis, A., Ledda, M., Renedo, M. B., Pavic, K., Gaigneaux, A., Glaab, E., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c02129 · Cited by 23 · see citing works

Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions

Zhang, Y., Meng, X., Tang, H., Cheng, M., Yang, F., & Xu, W. (2019) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2019.1702653 · Cited by 23 · see citing works

A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology

Sciver, R. E. V., Lee, M., Lee, C. G. L., Lafever, A., Svyatova, E. A., Kanda, K., Collier, A. L., van Reesema, L. L. S., Tang-Tan, A. M., Zheleva, V. P., et al. (2018) · Cancers · doi:10.3390/cancers10050142 · Cited by 21 · see citing works

Insight into Thermodynamic and Kinetic Profiles in Small-Molecule Optimization

Liu, W., Jiang, J., Lin, Y., You, Q., & Wang, L. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00682 · Cited by 20 · see citing works

Hydrophobic Tagging-Induced Degradation of PDEδ in Colon Cancer Cells

Guo, M., He, S., Cheng, J., Li, Y., Dong, G., & Sheng, C. (2022) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.1c00670 · Cited by 20 · see citing works

Discovery of novel KRAS‒PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

Chen, L., Zhang, J., Wang, X., Li, Y., Zhou, L., Lu, X., Dong, G., & Sheng, C. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.07.009 · Cited by 20 · see citing works

Selected Approaches to Disrupting Protein–Protein Interactions within the MAPK/RAS Pathway

Harwood, S. J., Smith, C. R., Lawson, J. D., & Ketcham, J. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087373 · Cited by 16 · see citing works

Au-24 as a potential thioredoxin reductase inhibitor in hepatocellular carcinoma cells

Dong, G., Ye, X., Wang, S., Li, W., Cai, R., Du, L., Shi, X., & Li, M. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106113 · Cited by 12 · see citing works

DFT and molecular simulation validation of the binding activity of PDEδ inhibitors for repression of oncogenic k-Ras

Majrashi, T. A., Sabt, A., Almahli, H., Hassab, M. A. E., Noamaan, M. A., Elkaeed, E. B., Hamissa, M. F., Maslamani, A. N. J., Shaldam, M. A., & Eldehna, W. M. (2024) · PLoS ONE · doi:10.1371/journal.pone.0300035 · Cited by 11 · see citing works

Covalent fragment mapping of KRasG12C revealed novel chemotypes with in vivo potency

Orgován, Z., Péczka, N., Petri, L., Ábrányi‐Balogh, P., Ranđelović, I., Tóth, S., Szakács, G., Nyíri, K., Vértessy, B. G., Pálfy, G., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115212 · Cited by 10 · see citing works

Discovery of Turn-On Fluorescent Probes for Detecting PDEδ Protein in Living Cells and Tumor Slices

Dong, G., Chen, L., Zhang, J., Liu, T., Du, L., Sheng, C., & Li, M. (2020) · Analytical Chemistry · doi:10.1021/acs.analchem.0c00335 · Cited by 9 · see citing works

Pd(II)-Catalyzed Cascade Annulation of o-Aminobenzoic Acids with CO, Amines, and Aldehydes to N3-/N1,N3-Substituted 2,3-Dihydroquinazolin-4(1H)-ones

Zhang, X., Wang, J., Xu, J., Pang, Q., Liu, D., & Zhang, G. (2023) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.3c00802 · Cited by 8 · see citing works

An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review

Sabt, A., Tawfik, H. O., Khaleel, E. F., Badi, R. M., Ibrahim, H. A. A., Elkaeed, E. B., & Eldehna, W. M. (2024) · Molecular Diversity · doi:10.1007/s11030-023-10777-6 · Cited by 7 · see citing works

Structural insights, regulation, and recent advances of RAS inhibitors in the MAPK signaling cascade: a medicinal chemistry perspective

Prajapati, V., Singh, A. K., Kumar, A. M., Singh, H., Pathak, P., Grishina, M., Kumar, V., Khalilullah, H., Verma, A., & Kumar, P. (2025) · RSC Medicinal Chemistry · doi:10.1039/d4md00923a · Cited by 6 · see citing works

Blocking TRIM47-mediated HNF4α degradation suppresses hepatocellular carcinoma progression

Hong, H., Xiao, M., Qian, H., Tan, S., Wu, S., Liu, F., Hong, X., Liu, S., Ding, C., Wang, K., et al. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.10.045 · Cited by 5 · see citing works

Recent Advances in Developing K-Ras Plasma Membrane Localization Inhibitors

Ye, N., Xu, Q., Li, W., Wang, P., & Zhou, J. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190902145116 · Cited by 5 · see citing works

Imidazoles

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Predicting the Likelihood of Molecules to Act as Modulators of Protein–Protein Interactions

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Targeting a Glutamic Acid in PDEδ with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling

Zhang, R., Huetzen, M. A., Binici, A., Martín‐Gago, P., Gasper, R., Rudashevskaya, E. L., Liu, J., Nagaraju, C., Reckzeh, E. S., Stuedle, A. S. T., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02082 · Cited by 2 · see citing works

Active fragment assembly strategy enabling fast discovery of KRAS inhibitors against pancreatic cancer cells

Zhang, P., Kong, L., Meng, X., Chen, Y., Jiao, Y., Su, Z., Song, X., Ding, K., & Xia, G. (2026) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2026.118807 · Cited by 1 · see citing works

Small-Molecule Inhibitors of Protein–Protein Interactions as Therapeutics

Poluri, K. M., Gulati, K., Tripathi, D. K., & Nagar, N. (2023) · Springer eBooks · doi:10.1007/978-981-99-2423-3_7 · Cited by 1 · see citing works

BindingDB Entry 50009544: Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction.

BindingDB (2021) · UC San Diego · doi:10.7270/q2ff3wts

BindingDB Entry 50021942: An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth.

BindingDB (2025) · UC San Diego · doi:10.7270/q2n01c64

BindingDB Entry 50010796: Discovery of Novel PDEδ Degraders for the Treatment of KRAS Mutant Colorectal Cancer.

BindingDB (2021) · UC San Diego · doi:10.7270/q2rn3cfh

BindingDB Entry 50008548: Fragment-to-Lead Medicinal Chemistry Publications in 2018.

BindingDB (2021) · UC San Diego · doi:10.7270/q2zg6wm7

BindingDB Entry 50020071: Discovery of Novel PDEδ Autophagic Degraders: A Case Study of Autophagy-Tethering Compound (ATTEC).

BindingDB (2024) · UC San Diego · doi:10.7270/q2bv7n19

BindingDB Entry 50015183: Hydrophobic Tagging-Induced Degradation of PDEδ in Colon Cancer Cells.

BindingDB (2023) · UC San Diego · doi:10.7270/q2pc368t

Discovery of novel KRAS‒PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

Chen, L., Zhang, J., Wang, X., Li, Y., Zhou, L., Lu, X., Dong, G., & Sheng, C. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.07.009 · Cited by 20 · see citing works

Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction

Chen, D., Chen, Y., Lian, F., Chen, L., Li, Y., Cao, D., Wang, X., Chen, L., Li, J., Meng, T., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.12.018 · Cited by 31 · see citing works

Discovery of Novel PDEδ Degraders for the Treatment of KRAS Mutant Colorectal Cancer

Cheng, J., Li, Y., Wang, X., Dong, G., & Sheng, C. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00929 · Cited by 67 · see citing works

Characterization of EZH2 as therapeutic target in pancreatic cancer

Witte, H., Kopp, W., Reutlinger, K., Ellenrieder, V., & Heßmann, E. (2016) · Pancreatology · doi:10.1016/j.pan.2016.05.042

Structural Biology-Inspired Discovery of Novel KRAS–PDEδ Inhibitors

Jiang, Y., Zhuang, C., Chen, L., Lu, J., Dong, G., Miao, Z., Zhang, W., Li, J., & Sheng, C. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01243 · Cited by 34 · see citing works