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

被引：1

作者：

Jarusiewicz, Jamie A. ^{[1
]}

Yoshimura, Satoshi ^{[2
]}

Actis, Marisa ^{[1
]}

Li, Yong ^{[1
]}

Fu, Xiang ^{[1
]}

Yang, Lei ^{[1
]}

Narina, Shilpa ^{[3
,4
]}

Pruett-Miller, Shondra M. ^{[3
,4
]}

Zhou, Suiping ^{[5
]}

Wang, Xusheng ^{[5
]}

High, Anthony A. ^{[5
]}

Nishiguchi, Gisele ^{[1
]}

Yang, Jun J. ^{[2
]}

Rankovic, Zoran ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Pharm & Pharmaceut Sci, Memphis, TN 38105 USA

[3] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, Memphis, TN 38105 USA

[4] St Jude Childrens Res Hosp, Ctr Adv Genome Engn, Memphis, TN 38105 USA

[5] St Jude Childrens Res Hosp, Ctr Proteom & Metabol, Memphis, TN 38105 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 14期

关键词：

PROTEIN; ABSORPTION;

D O I：

10.1021/acs.jmedchem.4c00481

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：11868 / 11884

页数：17

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