PDE6D Inhibitors with a New Design Principle Selectively Block K-Ras Activity
Open accessAbstract
The trafficking chaperone PDE6D (also referred to as PDEδ) has been nominated as a surrogate target for K-Ras4B (hereafter K-Ras). Arl2-assisted unloading of K-Ras from PDE6D in the perinuclear area is significant for correct K-Ras localization and therefore activity. However, the unloading mechanism also leads to the undesired ejection of PDE6D inhibitors. To counteract ejection, others have recently optimized inhibitors for picomolar affinities; however, cell penetration generally seems to remain an issue. To increase resilience against ejection, we engineered a “chemical spring” into prenyl-binding pocket inhibitors of PDE6D. Furthermore, cell penetration was improved by attaching a cell-penetration group, allowing us to arrive at micromolar in cellulo potencies in the first generation. Our model compounds, Deltaflexin-1 and -2, selectively disrupt K-Ras, but not H-Ras membrane organization. This selectivity profile is reflected in the antiproliferative activity on colorectal and breast cancer cells, as well as the ability to block stemness traits of lung and breast cancer cells. While our current model compounds still have a low in vitro potency, we expect that our modular and simple inhibitor redesign could significantly advance the development of pharmacologically more potent compounds against PDE6D and related targets, such as UNC119 in the future.
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Deltaflexin selectively inhibits oncogenic KRAS-driven cell proliferation and tumor formation.
“Moreover, deltaflexin selectively inhibits oncogenic KRAS-driven cell proliferation and tumor formation.348”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [348]
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Development and validation of a genetic algorithm for flexible docking 1 1Edited by F. E. Cohen
Jones, G., Willett, P., Glen, R. C., Leach, A. R., & Taylor, R. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0897 · Cited by 6,763 · see citing works
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557 · see citing works
The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity
Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1694-1 · Cited by 2,277 · see citing works
Lessons from the Cancer Genome
Garraway, L. A., & Lander, E. S. (2013) · Cell · doi:10.1016/j.cell.2013.03.002 · Cited by 1,322 · see citing works
Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172 · see citing works
Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition
Taipale, M., Krykbaeva, I., Koeva, M., Kayatekin, C., Westover, K. D., Karras, G. I., & Lindquist, S. (2012) · Cell · doi:10.1016/j.cell.2012.06.047 · Cited by 879 · see citing works
Integrative clinical genomics of metastatic cancer
Robinson, D. R., Wu, Y.-M., Lonigro, R. J., Vats, P., Cobain, E., Everett, J., Cao, X., Rabban, E., Kumar-Sinha, C., Raymond, V., et al. (2017) · Nature · doi:10.1038/nature23306 · Cited by 863 · see citing works
Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Lito, P., Solomon, M., Li, L.-S., Hansen, R., & Rosen, N. (2016) · Science · doi:10.1126/science.aad6204 · Cited by 691 · see citing works
Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling
Zimmermann, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S. A., Triola, G., Wittinghofer, A., Bastiaens, P. I. H., et al. (2013) · Nature · doi:10.1038/nature12205 · Cited by 596 · see citing works
Prodrugs of Phosphates and Phosphonates
Hecker, S. J., & Erion, M. D. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701260b · Cited by 414 · see citing works
Papke, B., & Der, C. J. (2017) · Science · doi:10.1126/science.aam7622 · Cited by 399 · see citing works
Hillig, R. C., Sautier, B., Schroeder, J., Moosmayer, D., Hilpmann, A., Stegmann, C. M., Werbeck, N. D., Briem, H., Boemer, U., Weiske, J., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1812963116 · Cited by 388 · see citing works
Yadav, B., Pemovska, T., Szwajda, A., Kulesskiy, E., Kontro, M., Karjalainen, R., Majumder, M. M., Malani, D., Murumägi, A., Knowles, J., et al. (2014) · Scientific Reports · doi:10.1038/srep05193 · Cited by 350 · see citing works
Chandra, A., Grecco, H. E., Pisupati, V., Perera, D., Cassidy, L., Skoulidis, F., Ismail, S. A., Hedberg, C., Hanzal-Bayer, M., Venkitaraman, A. R., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2394 · Cited by 325 · see citing works
Shima, F., Yoshikawa, Y., Ye, M., Araki, M., Matsumoto, S., Liao, J., Hu, L., Sugimoto, T., Ijiri, Y., Takeda, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217730110 · Cited by 293 · see citing works
Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo
Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. H., & Wittinghofer, A. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.686 · Cited by 252 · see citing works
Schmick, M., Vartak, N., Papke, B., Kovacevic, M., Truxius, D. C., Rossmannek, L., & Bastiaens, P. I. H. (2014) · Cell · doi:10.1016/j.cell.2014.02.051 · Cited by 243 · see citing works
Lerner, E. C., Zhang, T.-T., Knowles, D. B., Qian, Y., Hamilton, A. D., & Sebti, S. M. (1997) · Oncogene · doi:10.1038/sj.onc.1201296 · Cited by 239 · see citing works
ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting
Humbert, M. C., Weihbrecht, K., Searby, C. C., Li, Y., Pope, R. M., Sheffield, V. C., & Seo, S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1210916109 · Cited by 228 · see citing works
K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif
Tsai, F. D., Lopes, M. S., Zhou, M., Court, H., Ponce, O., Fiordalisi, J. J., Gierut, J. J., Cox, A. D., Haigis, K. M., & Philips, M. R. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1412811112 · Cited by 226 · see citing works
Small-molecule modulation of Ras signaling
Spiegel, J., Cromm, P. M., Zimmermann, G., Grossmann, T. N., & Waldmann, H. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1560 · Cited by 215 · see citing works
Sun, J., Blaskovich, M. A., Knowles, D. B., Qian, Y., Ohkanda, J., Bailey, R. D., Hamilton, A. D., & Sebti, S. M. (1999) · PubMed · Cited by 210 · see citing works
Maximizing the Therapeutic Potential of HSP90 Inhibitors
Butler, L. M., Ferraldeschi, R., Armstrong, H., Centenera, M. M., & Workman, P. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0234 · Cited by 208 · see citing works
Winter-Vann, A. M., Baron, R. A., Wong, W., dela Cruz, J., York, J. D., Gooden, D. M., Bergo, M. O., Young, S. G., Toone, E. J., & Casey, P. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408107102 · Cited by 178 · see citing works
Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ
Dharmaiah, S., Bindu, L. K., Tran, T. H., Gillette, W., Frank, P. H., Ghirlando, R., Nissley, D. V., Esposito, D., McCormick, F. P., Stephen, A. G., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1615316113 · Cited by 176 · see citing works
Self-citationIdentification of pyrazolopyridazinones as PDEδ inhibitors
Papke, B., Murarka, S., Vogel, H. A., Martín‐Gago, P., Kovačević, M., Truxius, D. C., Fansa, E. K., Ismail, S., Zimmermann, G., Heinelt, K. F., et al. (2016) · Nature Communications · doi:10.1038/ncomms11360 · Cited by 164 · see citing works
Guen, V. J., Chavarria, T. E., Kröger, C., Ye, X., Weinberg, R. A., & Lees, J. A. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1711534114 · Cited by 145 · see citing works
Thomas, S., Wright, K. J., Corre, S. L., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., et al. (2013) · Human Mutation · doi:10.1002/humu.22470 · Cited by 123 · see citing works
Prakash, P., Sayyed–Ahmad, A., Cho, K.-J., Dolino, D. M., Chen, W., Li, H., Grant, B. J., Hancock, J. F., & Gorfe, A. A. (2017) · Scientific Reports · doi:10.1038/srep40109 · Cited by 93 · see citing works
Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding
McCarthy, M. J., Pagba, C. V., Prakash, P., Naji, A. K., van der Hoeven, D., Liang, H., Gupta, A. K., Zhou, Y., Cho, K.-J., Hancock, J. F., et al. (2019) · ACS Omega · doi:10.1021/acsomega.8b03308 · Cited by 90 · see citing works
Characterizing cancer cells with cancer stem cell-like features in 293T human embryonic kidney cells
Debeb, B. G., Zhang, X., Krishnamurthy, S., Gao, H., Cohen, E. N., Li, L., Rodriguez, A. A., Landis, M. D., Lucci, A., Ueno, N. T., et al. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-180 · Cited by 89 · see citing works
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
Cancer stem cell drugs target K-ras signaling in a stemness context
Najumudeen, A. K., Jaiswal, A., Lectez, B. L. P., Oetken-Lindholm, C., Guzmán, C., Siljamäki, E., Posada, I. M. D., Lacey, E., Aittokallio, T. A., & Abankwa, D. (2016) · Oncogene · doi:10.1038/onc.2016.59 · Cited by 84 · see citing works
Self-citationGillette, W., Esposito, D., Blanco, M. A., Alexander, P., Bindu, L. K., Bittner, C., Chertov, O., Frank, P. H., Grose, C., Jones, J. E., et al. (2015) · Scientific Reports · doi:10.1038/srep15916 · Cited by 80 · see citing works
Self-citationPDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity
Fansa, E. K., Kösling, S. K., Zent, E., Wittinghofer, A., & Ismail, S. (2016) · Nature Communications · doi:10.1038/ncomms11366 · Cited by 80 · see citing works
Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering
Blaževitš, O., Mideksa, Y. G., Šolman, M., Ligabue, A., Ariotti, N., Nakhaeizadeh, H., Fansa, E. K., Papageorgiou, A. C., Wittinghofer, A., Ahmadian, M. R., et al. (2016) · Scientific Reports · doi:10.1038/srep24165 · Cited by 74 · see citing works
Self-citationKRAS Prenylation Is Required for Bivalent Binding with Calmodulin in a Nucleotide-Independent Manner
Agamasu, C., Ghirlando, R., Taylor, T. E., Messing, S. A. J., Tran, T. H., Bindu, L. K., Tonelli, M., Nissley, D. V., McCormick, F. P., & Stephen, A. G. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.02.004 · Cited by 52 · see citing works
Self-citationGuzmán, C., Šolman, M., Ligabue, A., Blaževitš, O., Andrade, D. M., Reymond, L., Eggeling, C., & Abankwa, D. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.537001 · Cited by 50 · see citing works
Self-citationGuzmán, C., Oetken-Lindholm, C., & Abankwa, D. (2015) · SLAS TECHNOLOGY · doi:10.1177/2211068215606048 · Cited by 33 · see citing works
Self-citationFragment-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
Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner
Posada, I. M. D., Lectez, B. L. P., Sharma, M., Oetken-Lindholm, C., Yetukuri, L., Zhou, Y., Aittokallio, T. A., & Abankwa, D. (2017) · Oncotarget · doi:10.18632/oncotarget.17819 · Cited by 25 · see citing works
Self-citationKiuru, E., Ahmed, Z., Lönnberg, H., et al. (2012) · The Journal of Organic Chemistry · doi:10.1021/jo302421u · Cited by 20 · see citing works
Small‐Molecule Inhibition of the UNC119–Cargo Interaction
Mejuch, T., Garivet, G., Hofer, W., Kaiser, N., Fansa, E. K., Ehrt, C., Koch, O., Baumann, M., Ziegler, S., Wittinghofer, A., et al. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201701905 · Cited by 19 · see citing works
Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
Posada, I. M. D., Lectez, B. L. P., Siddiqui, F. A., Oetken-Lindholm, C., Sharma, M., & Abankwa, D. (2017) · Scientific Reports · doi:10.1038/s41598-017-09387-8 · Cited by 13 · see citing works
Self-citationSmall‐Molecule Inhibition of the UNC119–Cargo Interaction
Mejuch, T., Garivet, G., Hofer, W., Kaiser, N., Fansa, E. K., Ehrt, C., Koch, O., Baumann, M., Ziegler, S., Wittinghofer, A., et al. (2017) · Angewandte Chemie · doi:10.1002/ange.201701905 · Cited by 7 · see citing works
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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
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
- Authors
- Siddiqui, F. A., Alam, C., Rosenqvist, P., Ora, M., Sabt, A., Manoharan, G. B., Bindu, L., Okutachi, S., Catillon, M., Taylor, T., Abdelhafez, O. M., Lönnberg, H., Stephen, A. G., Papageorgiou, A. C., Virta, P., & Abankwa, D.
- Affiliations
- Åbo Akademi University (FI)
- University of Turku (FI)
- University of Luxembourg (LU)
- Frederick National Laboratory for Cancer Research (US)
- National Research Centre (EG)
- University of Turku , , ,
- Corresponding author
- Abankwa, Daniel
- ORCID
- Venue
- ACS Omega
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-12-23
- Volume
- 5
- Issue
- 1
- Pages
- 832-842
- ISSN
- 2470-1343 (ISSN-L)
- PMC
- PMC6964506
- OpenAlex
- W2994739605
- Cited by
- 46
- References
- 45
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 9 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 5
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- ACS Omega (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Output (Edinburgh Napier University) (publishedVersion, other-oa)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-nd)
- UTUPub (University of Turku) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Åbo Akademi University Research Portal (submittedVersion, cc-by-nc-nd)
- Edinburgh Napier Research Repository (Edinburgh Napier University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Cancer Institute (HHSN261200800001E)
- Sigrid Juséliuksen Säätiö
- Kansainvälisen Liikkuvuuden ja Yhteistyön Keskus
- Syöpäjärjestöt
- Academy of Finland (304638, 308931)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- PDE6D, KRAS, K-Ras4B, RAS inhibitors, ARL2, cancer stemness, colorectal cancer, breast cancer, lung cancer, UNC119
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