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.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Biological Availability
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Cell Line, Tumor
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Humans
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)* / antagonists & inhibitors
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)* / metabolism
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Mice
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / metabolism
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Structure-Activity Relationship
Substances
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Protein Kinase Inhibitors
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Antineoplastic Agents
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LCK protein, human