A novel small molecule, CU05-1189, targeting the pleckstrin homology domain of PDK1 suppresses VEGF-mediated angiogenesis and tumor growth by blocking the Akt signaling pathway
Inhibition of angiogenesis is considered a promising therapeutic approach for cancer treatment. Our previous genetic research showed that the use of a cell-penetrating peptide to inhibit the pleckstrin homology (PH) domain of 3-phosphoinositide-dependent kinase 1 (PDK1) was a viable approach to supp...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1275749/full |
| _version_ | 1797626713101828096 |
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| author | Jeongeun Park Haiying Zhang Hyun Jung Kwak Changdev Gorakshnath Gadhe Yeomyeong Kim Hyejeong Kim Minyoung Noh Dongyun Shin Sang-Jun Ha Young-Guen Kwon |
| author_facet | Jeongeun Park Haiying Zhang Hyun Jung Kwak Changdev Gorakshnath Gadhe Yeomyeong Kim Hyejeong Kim Minyoung Noh Dongyun Shin Sang-Jun Ha Young-Guen Kwon |
| author_sort | Jeongeun Park |
| collection | DOAJ |
| description | Inhibition of angiogenesis is considered a promising therapeutic approach for cancer treatment. Our previous genetic research showed that the use of a cell-penetrating peptide to inhibit the pleckstrin homology (PH) domain of 3-phosphoinositide-dependent kinase 1 (PDK1) was a viable approach to suppress pathological angiogenesis. Herein, we synthesized and characterized a novel small molecule, CU05-1189, based on our prior study and present evidence for the first time that this compound possesses antiangiogenic properties both in vitro and in vivo. The computational analysis showed that CU05-1189 can interact with the PH domain of PDK1, and it significantly inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, and tube formation in human umbilical vein endothelial cells without apparent toxicity. Western blot analysis revealed that the Akt signaling pathway was specifically inhibited by CU05-1189 upon VEGF stimulation, without affecting other VEGF receptor 2 downstream molecules or cytosolic substrates of PDK1, by preventing translocation of PDK1 to the plasma membrane. We also found that CU05-1189 suppressed VEGF-mediated vascular network formation in a Matrigel plug assay. More importantly, CU05-1189 had a good pharmacokinetic profile with a bioavailability of 68%. These results led to the oral administration of CU05-1189, which resulted in reduced tumor microvessel density and growth in a xenograft mouse model. Taken together, our data suggest that CU05-1189 may have great potential and be a promising lead as a novel antiangiogenic agent for cancer treatment. |
| first_indexed | 2024-03-11T10:14:06Z |
| format | Article |
| id | doaj.art-c960638ed2504fbb88d84d46bfceccf6 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-11T10:14:06Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-c960638ed2504fbb88d84d46bfceccf62023-11-16T12:27:24ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-11-011410.3389/fphar.2023.12757491275749A novel small molecule, CU05-1189, targeting the pleckstrin homology domain of PDK1 suppresses VEGF-mediated angiogenesis and tumor growth by blocking the Akt signaling pathwayJeongeun Park0Haiying Zhang1Hyun Jung Kwak2Changdev Gorakshnath Gadhe3Yeomyeong Kim4Hyejeong Kim5Minyoung Noh6Dongyun Shin7Sang-Jun Ha8Young-Guen Kwon9Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of KoreaDepartment of Bio Research, Curacle Co., Ltd., Seoul, Republic of KoreaDepartment of Strategic Planning, Curacle Co., Ltd., Seoul, Republic of KoreaDepartment of New Drug Research Development, Curacle Co., Ltd., Seoul, Republic of KoreaDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of KoreaDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of KoreaDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of KoreaCollege of Pharmacy, Gachon University, Incheon, Republic of KoreaDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of KoreaDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of KoreaInhibition of angiogenesis is considered a promising therapeutic approach for cancer treatment. Our previous genetic research showed that the use of a cell-penetrating peptide to inhibit the pleckstrin homology (PH) domain of 3-phosphoinositide-dependent kinase 1 (PDK1) was a viable approach to suppress pathological angiogenesis. Herein, we synthesized and characterized a novel small molecule, CU05-1189, based on our prior study and present evidence for the first time that this compound possesses antiangiogenic properties both in vitro and in vivo. The computational analysis showed that CU05-1189 can interact with the PH domain of PDK1, and it significantly inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, and tube formation in human umbilical vein endothelial cells without apparent toxicity. Western blot analysis revealed that the Akt signaling pathway was specifically inhibited by CU05-1189 upon VEGF stimulation, without affecting other VEGF receptor 2 downstream molecules or cytosolic substrates of PDK1, by preventing translocation of PDK1 to the plasma membrane. We also found that CU05-1189 suppressed VEGF-mediated vascular network formation in a Matrigel plug assay. More importantly, CU05-1189 had a good pharmacokinetic profile with a bioavailability of 68%. These results led to the oral administration of CU05-1189, which resulted in reduced tumor microvessel density and growth in a xenograft mouse model. Taken together, our data suggest that CU05-1189 may have great potential and be a promising lead as a novel antiangiogenic agent for cancer treatment.https://www.frontiersin.org/articles/10.3389/fphar.2023.1275749/fullCU05-1189angiogenesisPDK1Aktcancer therapy |
| spellingShingle | Jeongeun Park Haiying Zhang Hyun Jung Kwak Changdev Gorakshnath Gadhe Yeomyeong Kim Hyejeong Kim Minyoung Noh Dongyun Shin Sang-Jun Ha Young-Guen Kwon A novel small molecule, CU05-1189, targeting the pleckstrin homology domain of PDK1 suppresses VEGF-mediated angiogenesis and tumor growth by blocking the Akt signaling pathway Frontiers in Pharmacology CU05-1189 angiogenesis PDK1 Akt cancer therapy |
| title | A novel small molecule, CU05-1189, targeting the pleckstrin homology domain of PDK1 suppresses VEGF-mediated angiogenesis and tumor growth by blocking the Akt signaling pathway |
| title_full | A novel small molecule, CU05-1189, targeting the pleckstrin homology domain of PDK1 suppresses VEGF-mediated angiogenesis and tumor growth by blocking the Akt signaling pathway |
| title_fullStr | A novel small molecule, CU05-1189, targeting the pleckstrin homology domain of PDK1 suppresses VEGF-mediated angiogenesis and tumor growth by blocking the Akt signaling pathway |
| title_full_unstemmed | A novel small molecule, CU05-1189, targeting the pleckstrin homology domain of PDK1 suppresses VEGF-mediated angiogenesis and tumor growth by blocking the Akt signaling pathway |
| title_short | A novel small molecule, CU05-1189, targeting the pleckstrin homology domain of PDK1 suppresses VEGF-mediated angiogenesis and tumor growth by blocking the Akt signaling pathway |
| title_sort | novel small molecule cu05 1189 targeting the pleckstrin homology domain of pdk1 suppresses vegf mediated angiogenesis and tumor growth by blocking the akt signaling pathway |
| topic | CU05-1189 angiogenesis PDK1 Akt cancer therapy |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1275749/full |
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