Development of an Orally Bioavailable LCK PROTAC Degrader as a Potential Therapeutic Approach to T-Cell Acute Lymphoblastic Leukemia.

Autor:	Jarusiewicz JA; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Yoshimura S; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Actis M; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Li Y; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Fu X; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Yang L; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Narina S; Department of Cell and Molecular Biology and Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Pruett-Miller SM; Department of Cell and Molecular Biology and Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Zhou S; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Wang X; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., High AA; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Nishiguchi G; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Yang JJ; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Rankovic Z; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jul 25; Vol. 67 (14), pp. 11868-11884. Date of Electronic Publication: 2024 Jul 08.
DOI:	10.1021/acs.jmedchem.4c00481
Abstrakt:	Despite significant advances over recent years, the treatment of T cell acute lymphoblastic leukemia (T-ALL) remains challenging. We have recently shown that a subset of T-ALL cases exhibited constitutive activation of the lymphocyte-specific protein tyrosine kinase (LCK) and were consequently responsive to treatments with LCK inhibitors and degraders such as dasatinib and dasatinib-based PROTACs. Here we report the design, synthesis and in vitro/vivo evaluation of SJ45566, a potent and orally bioavailable LCK PROTAC.
Databáze:	MEDLINE
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