Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia,Journal of Medicinal Chemistry

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Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-22 , DOI: 10.1021/acs.jmedchem.1c00804
Nicole Bata ₁ , Apirat Chaikuad _{2,

3} , Nicole A Bakas ₁ , Allison S Limpert ₁ , Lester J Lambert ₁ , Douglas J Sheffler ₁ , Lena M Berger _{2,

3} , Guoxiong Liu ₄ , Cunxiang Yuan ₄ , Li Wang ₄ , Yi Peng ₄ , Jing Dong ₄ , Maria Celeridad ₁ , Fabiana Layng ₁ , Stefan Knapp _{2,

3,

5} , Nicholas D P Cosford ₁

Affiliation

Serine/threonine-protein kinases 3 and 4 (STK3 and STK4, respectively) are key components of the Hippo signaling pathway, which regulates cell proliferation and death and provides a potential therapeutic target for acute myeloid leukemia (AML). Herein, we report the structure-based design of a series of pyrrolopyrimidine derivatives as STK3 and STK4 inhibitors. In an initial screen, the compounds exhibited low nanomolar potency against both STK3 and STK4. Crystallization of compound 6 with STK4 revealed two-point hinge binding in the ATP-binding pocket. Further characterization and analysis demonstrated that compound 20 (SBP-3264) specifically inhibited the Hippo signaling pathway in cultured mammalian cells and possessed favorable pharmacokinetic and pharmacodynamic properties in mice. We show that genetic knockdown and pharmacological inhibition of STK3 and STK4 suppress the proliferation of AML cells in vitro. Thus, SBP-3264 is a valuable chemical probe for understanding the roles of STK3 and STK4 in AML and is a promising candidate for further advancement as a potential therapy.

中文翻译：

Hippo 通路激酶 STK3/MST2 和 STK4/MST1 的抑制剂可用于治疗急性髓性白血病

丝氨酸/苏氨酸蛋白激酶 3 和 4（分别为 STK3 和 STK4）是 Hippo 信号通路的关键组成部分，它调节细胞增殖和死亡，并为急性髓性白血病 (AML) 提供潜在的治疗靶点。在此，我们报告了一系列作为 STK3 和 STK4 抑制剂的吡咯并嘧啶衍生物的基于结构的设计。在初步筛选中，这些化合物对 STK3 和 STK4 均表现出低纳摩尔效力。化合物6与 STK4 的结晶揭示了 ATP 结合口袋中的两点铰链结合。进一步的表征和分析表明，化合物20(SBP-3264) 特异性抑制培养的哺乳动物细胞中的 Hippo 信号通路，并在小鼠中具有良好的药代动力学和药效学特性。我们表明 STK3 和 STK4 的基因敲低和药理学抑制抑制了体外 AML 细胞的增殖。因此，SBP-3264 是一种有价值的化学探针，可用于了解 STK3 和 STK4 在 AML 中的作用，并且是作为潜在疗法进一步发展的有希望的候选者。

更新日期：2022-01-27

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