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

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Development of an Orally Bioavailable LCK PROTAC Degrader as a Potential Therapeutic Approach to T-Cell Acute Lymphoblastic Leukemia
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-08 , DOI: 10.1021/acs.jmedchem.4c00481
Jamie A Jarusiewicz ₁ , Satoshi Yoshimura ₂ , Marisa Actis ₁ , Yong Li ₁ , Xiang Fu ₁ , Lei Yang ₁ , Shilpa Narina ₃ , Shondra M Pruett-Miller ₃ , Suiping Zhou ₄ , Xusheng Wang ₄ , Anthony A High ₄ , Gisele Nishiguchi ₁ , Jun J Yang ₂ , Zoran Rankovic ₁

Affiliation

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.

中文翻译：

开发口服生物可利用的 LCK PROTAC 降解剂作为 T 细胞急性淋巴细胞白血病的潜在治疗方法

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。我们最近发现，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（例如达沙替尼和基于达沙替尼的 PROTAC）治疗有反应。在这里，我们报告了 SJ45566 的设计、合成和体外/体内评估，SJ45566 是一种有效的口服生物可利用的 LCK PROTAC。

更新日期：2024-07-08

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