دورية أكاديمية
أعرض في EDS

A selective BCL-X L PROTAC degrader achieves safe and potent antitumor activity.

التفاصيل البيبلوغرافية
العنوان: A selective BCL-X L PROTAC degrader achieves safe and potent antitumor activity.
المؤلفون: Khan S; Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA., Zhang X; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA., Lv D; Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA., Zhang Q; Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA., He Y; Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA., Zhang P; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA., Liu X; Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA., Thummuri D; Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA., Yuan Y; Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA., Wiegand JS; Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA., Pei J; Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA., Zhang W; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Sharma A; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA., McCurdy CR; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA., Kuruvilla VM; Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA., Baran N; Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA., Ferrando AA; Department of Pediatrics, Pathology, Cell Biology and Systems of Biology and Institute for Cancer Genetics, Columbia University, New York, NY, USA., Kim YM; Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA., Rogojina A; Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Houghton PJ; Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Huang G; Department of Medicine, the Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Hromas R; Department of Medicine, the Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Konopleva M; Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA., Zheng G; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA. zhengg@cop.ufl.edu., Zhou D; Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA. zhoudaohong@cop.ufl.edu.
المصدر: Nature medicine [Nat Med] 2019 Dec; Vol. 25 (12), pp. 1938-1947. Date of Electronic Publication: 2019 Dec 02.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
أسماء مطبوعة: Publication: New York Ny : Nature Publishing Company
Original Publication: New York, NY : Nature Pub. Co., [1995-
مواضيع طبية MeSH: Aniline Compounds/*pharmacology , Sulfonamides/*pharmacology , Thrombocytopenia/*drug therapy , Von Hippel-Lindau Tumor Suppressor Protein/*genetics , bcl-X Protein/*genetics, Aniline Compounds/chemistry ; Animals ; Antineoplastic Agents/pharmacology ; Blood Platelets/drug effects ; Blood Platelets/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Heterografts ; Humans ; Mice ; Proteolysis ; Sulfonamides/chemistry ; Thrombocytopenia/genetics ; Thrombocytopenia/pathology ; bcl-X Protein/antagonists & inhibitors
مستخلص: B-cell lymphoma extra large (BCL-X L ) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-X L inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-X L proteolysis-targeting chimera (PROTAC), that targets BCL-X L to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-X L -dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-X L .
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معلومات مُعتمدة: R35 CA210065 United States CA NCI NIH HHS; R01 GM109645 United States GM NIGMS NIH HHS; R01 CA211963 United States CA NCI NIH HHS; R01 CA219836 United States CA NCI NIH HHS; R01 CA200673 United States CA NCI NIH HHS; R21 CA223371 United States CA NCI NIH HHS; R01 CA203834 United States CA NCI NIH HHS; R01 CA205224 United States CA NCI NIH HHS; R01 CA242003 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Aniline Compounds)
0 (Antineoplastic Agents)
0 (BCL2L1 protein, human)
0 (Sulfonamides)
0 (bcl-X Protein)
EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
EC 6.3.2.- (VHL protein, human)
XKJ5VVK2WD (navitoclax)
تواريخ الأحداث: Date Created: 20191204 Date Completed: 20200127 Latest Revision: 20220420
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6898785
DOI: 10.1038/s41591-019-0668-z
PMID: 31792461
قاعدة البيانات: MEDLINE
الوصف
تدمد:1546-170X
DOI:10.1038/s41591-019-0668-z