Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
J Med Chem. 2024 Jul 25;67(14):11868-11884. doi: 10.1021/acs.jmedchem.4c00481. Epub 2024 Jul 8.
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 evaluation of SJ45566, a potent and orally bioavailable LCK PROTAC.
尽管近年来取得了重大进展，但 T 细胞急性淋巴细胞白血病（T-ALL）的治疗仍然具有挑战性。我们最近表明，一部分 T-ALL 病例表现出淋巴细胞特异性蛋白酪氨酸激酶（LCK）的组成性激活，因此对 LCK 抑制剂和降解剂（如达沙替尼和达沙替尼为基础的 PROTAC）的治疗有反应。在这里，我们报告了 SJ45566 的设计、合成和评价，这是一种有效的、口服生物利用的 LCK PROTAC。
