Preclinical evaluation of proteolytic targeting of LCK as a therapeutic approach in T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and there is an unmet need for targeted therapies, especially for patients with relapsed disease. We have recently identified pre-T cell receptor and lymphocyte-specific protein tyrosine kinase (LCK) signaling as...

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Vydáno v:Science translational medicine Ročník 14; číslo 659; s. eabo5228
Hlavní autoři: Hu, Jianzhong, Jarusiewicz, Jamie, Du, Guoqing, Nishiguchi, Gisele, Yoshimura, Satoshi, Panetta, John C, Li, Zhenhua, Min, Jaeki, Yang, Lei, Chepyala, Divyabharathi, Actis, Marisa, Reyes, Noemi, Smart, Brandon, Pui, Ching-Hon, Teachey, David T, Rankovic, Zoran, Yang, Jun J
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 24.08.2022
Témata:
Cell Line, Tumor
Dasatinib - pharmacology
Dasatinib - therapeutic use
Humans
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Proteolysis
T-Lymphocytes - metabolism
ISSN:1946-6242, 1946-6242
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Shrnutí:T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and there is an unmet need for targeted therapies, especially for patients with relapsed disease. We have recently identified pre-T cell receptor and lymphocyte-specific protein tyrosine kinase (LCK) signaling as a common therapeutic vulnerability in T-ALL. LCK inhibitor dasatinib showed efficacy against T-ALL in preclinical studies and in patients with T-ALL; however, this is transient in most cases. Leveraging the proteolysis targeting chimera (PROTAC) approach, we developed a series of LCK degraders using dasatinib as an LCK ligand and phenyl-glutarimide as a cereblon-directing moiety. Our lead compound SJ11646 exhibited marked efficiency in cereblon-mediated LCK degradation in T-ALL cells. Relative to dasatinib, SJ11646 showed up to three orders of magnitude higher cytotoxicity in LCK-activated T-ALL cell lines and primary leukemia samples in vitro, with drastically prolonged suppression of LCK signaling. In vivo pharmacokinetic and pharmacodynamic profiling indicated a 630% increase in the duration of LCK suppression by SJ11646 over dasatinib in patient-derived xenograft models of T-ALL, which translated into its extended leukemia-free survival over dasatinib in vivo. Last, SJ11646 retained a high binding affinity to 51 human kinases, particularly ABL1, KIT, and DDR1, all of which are known drug targets in other cancers. Together, our dasatinib-based phenyl-glutarimide PROTACs are promising therapeutic agents in T-ALL and valuable tools for developing degradation-based therapeutics for other cancers.
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ISSN:1946-6242
1946-6242
DOI:10.1126/scitranslmed.abo5228