Novel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1.

Autor:	Ryu S; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea., Park JE; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States., Ham YJ; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea., Lim DC; Koch Institute for Integrative Cancer Research, and Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, United States., Kwiatkowski NP; Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, United States.; Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States., Kim DH; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.; Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, 154 Gwanggyosan-ro, Yeongtong-gu, Suwon 16227, Republic of Korea., Bhunia D; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea., Kim ND; Voronoibio Inc., 32 Songdogwahak-ro, Yeonsu-gu, Incheon 21984, Republic of Korea., Yaffe MB; Koch Institute for Integrative Cancer Research, and Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, United States.; Divisions of Acute Care Surgery, Trauma, and Surgical Critical Care, and Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, United States., Son W; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea., Kim N; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea., Choi TI; Department of Biology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea., Swain P; Department of Biology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea., Kim CH; Department of Biology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea., Lee JY; Department of Biological Sciences, Keimyung University, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea., Gray NS; Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, Stanford School of Medicine, Stanford University, 290 Jane Stanford Way, Stanford, California 94305, United States., Lee KS; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States., Sim T; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Feb 10; Vol. 65 (3), pp. 1915-1932. Date of Electronic Publication: 2022 Jan 14.
DOI:	10.1021/acs.jmedchem.1c01359
Abstrakt:	The polo-box domain (PBD) of Plk1 is a promising target for cancer therapeutics. We designed and synthesized novel phosphorylated macrocyclic peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL. The inhibitory activities of 16e on Plk1-PBD is >30-fold higher than those of PMQSpTPL. Both 16a and 16e possess excellent selectivity for Plk1-PBD over Plk2/3-PBD. Analysis of the cocrystal structure of Plk1-PBD in complex with 16a reveals that the 3-(trifluoromethyl)benzoyl group in 16a interacts with Arg516 through a π-stacking interaction. This π-stacking interaction, which has not been reported previously, provides insight into the design of novel and potent Plk1-PBD inhibitors. Furthermore, 16h , a PEGlyated macrocyclic phosphopeptide derivative, induces Plk1 delocalization and mitotic failure in HeLa cells. Also, the number of phospho-H3-positive cells in a zebrafish embryo increases in proportion to the amount of 16a . Collectively, the novel macrocyclic peptidomimetics should serve as valuable templates for the design of potent and novel Plk1-PBD inhibitors.
Databáze:	MEDLINE
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