强效且选择性的Janus激酶2/3导向性PG-PROTAC的研发。
Development of Potent and Selective Janus Kinase 2/3 Directing PG-PROTACs.
作者信息
Alcock Lisa J, Chang Yunchao, Jarusiewicz Jamie A, Actis Marisa, Nithianantham Stanley, Mayasundari Anand, Min Jaeki, Maxwell Dylan, Hunt Jeremy, Smart Brandon, Yang Jun J, Nishiguchi Gisele, Fischer Marcus, Mullighan Charles G, Rankovic Zoran
机构信息
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
出版信息
ACS Med Chem Lett. 2022 Feb 21;13(3):475-482. doi: 10.1021/acsmedchemlett.1c00650. eCollection 2022 Mar 10.
Abstract
Aberrant activation of the JAK-STAT signaling pathway has been implicated in the pathogenesis of a range of hematological malignancies and autoimmune disorders. Here we describe the design, synthesis, and characterization of JAK2/3 PROTACs utilizing a phenyl glutarimide (PG) ligand as the cereblon (CRBN) recruiter. SJ10542 displayed high selectivity over GSPT1 and other members of the JAK family and potency in patient-derived ALL cells containing both JAK2 fusions and CRLF2 rearrangements.
摘要
JAK-STAT信号通路的异常激活与一系列血液系统恶性肿瘤和自身免疫性疾病的发病机制有关。在此，我们描述了利用苯基戊二酰亚胺（PG）配体作为脑啡肽（CRBN）招募剂的JAK2/3 PROTAC的设计、合成和表征。SJ10542对GSPT1和JAK家族的其他成员表现出高选择性，并对含有JAK2融合和CRLF2重排的患者来源的急性淋巴细胞白血病（ALL）细胞具有活性。
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