Proteolytic Targeting Chimeras (PROTACs) for Targeting LCK-driven Leukemia (SJ-21-0047)

St. Jude Reference #SJ-21-0047

Description

LCK is an emerging therapeutic target for T-ALL. Dasatinib, a small-molecule LCK inhibitor, has significant anti-leukemia efficacy in vitro and in vivo against T-ALL. However, these effects require constant dosing of dasatinib and drug resistance is common. The PROTACs we developed showed greater potency and longer-lasting effects than dasatinib in suppressing LCK signaling and thus better cytotoxity in LCK-dependent T-ALLs.

Researchers at St. Jude created a series of Proteolytic Targeting Chimera (PROTACs) compounds that can target LCK for degradation with dasatinib as the bait/ligand. LCK kinase is an important drug target in T-ALL and these PROTACs induce T-ALL apoptosis by complete degradation of therapeutic target LCK. 

Keywords

small molecule, drug, PROTAC. targeted protein degradation, Dasatinib, LCK inhibitor, leukemia, T-ALL, resistance.

Granted Patents or Published Applications

US application filed, WO published as 2023/096995.

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Gocho, Y., Liu, J., Hu, J. et al. Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia. Nat Cancer 2, 284–299 (2021). https://doi.org/10.1038/s43018-020-00167-4

Lisa J. Alcock, Yunchao Chang, Jamie A. Jarusiewicz, Marisa Actis, Stanley Nithianantham, Anand Mayasundari, Jaeki Min, Dylan Maxwell, Jeremy Hunt, Brandon Smart, Jun J. Yang, Gisele Nishiguchi, Marcus Fischer, Charles G. Mullighan, and Zoran Rankovic, “Development of Potent and Selective Janus Kinase 2/3 Directing PG–PROTACs,” ACS Medicinal Chemistry Letters 2022 13 (3), 475-482, DOI: 10.1021/acsmedchemlett.1c00650 https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.1c00650

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