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
  • 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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