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

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

  • J Med Chem. 2024 Jul 8. doi: 10.1021/acs.jmedchem.4c00481.
Jamie A Jarusiewicz 1,  Satoshi Yoshimura 2,  Marisa Actis 1,  Yong Li 1,  Xiang Fu 1,  Lei Yang 1,  Shilpa Narina 3,  Shondra M Pruett-Miller 3,  Suiping Zhou 4,  Xusheng Wang 4,  Anthony A High 4,  Gisele Nishiguchi 1,  Jun J Yang 2,  Zoran Rankovic 1
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 2 Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 3 Department of Cell and Molecular Biology and Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 4 Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
PMID: 38973320 DOI: 10.1021/acs.jmedchem.4c00481
Abstract

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.

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