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Targeting Pim Kinases and DAPK3 to Control Hypertension
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-07-19 , DOI: 10.1016/j.chembiol.2018.06.006 David A Carlson 1 , Miriam R Singer 1 , Cindy Sutherland 2 , Clara Redondo 3 , Leila T Alexander 3 , Philip F Hughes 1 , Stefan Knapp 4 , Susan B Gurley 5 , Matthew A Sparks 5 , Justin A MacDonald 2 , Timothy A J Haystead 1
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-07-19 , DOI: 10.1016/j.chembiol.2018.06.006 David A Carlson 1 , Miriam R Singer 1 , Cindy Sutherland 2 , Clara Redondo 3 , Leila T Alexander 3 , Philip F Hughes 1 , Stefan Knapp 4 , Susan B Gurley 5 , Matthew A Sparks 5 , Justin A MacDonald 2 , Timothy A J Haystead 1
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Sustained vascular smooth muscle hypercontractility promotes hypertension and cardiovascular disease. The etiology of hypercontractility is not completely understood. New therapeutic targets remain vitally important for drug discovery. Here we report that Pim kinases, in combination with DAPK3, regulate contractility and control hypertension. Using a co-crystal structure of lead molecule (HS38) in complex with DAPK3, a dual Pim/DAPK3 inhibitor (HS56) and selective DAPK3 inhibitors (HS94 and HS148) were developed to provide mechanistic insight into the polypharmacology of hypertension.In vitroandex vivostudies indicated that Pim kinases directly phosphorylate smooth muscle targets and that Pim/DAPK3 inhibition, unlike selective DAPK3 inhibition, significantly reduces contractility.In vivo, HS56 decreased blood pressure in spontaneously hypertensive mice in a dose-dependent manner without affecting heart rate. These findings suggest including Pim kinase inhibition within a multi-target engagement strategy for hypertension management. HS56 represents a significant step in the development of molecularly targeted antihypertensive medications.
中文翻译：
靶向 Pim 激酶和 DAPK3 控制高血压
持续的血管平滑肌收缩过度会促进高血压和心血管疾病。收缩过度的病因尚不完全清楚。新的治疗靶点对于药物发现仍然至关重要。在这里，我们报道 Pim 激酶与 DAPK3 结合，调节收缩力并控制高血压。利用先导分子 (HS38) 与 DAPK3 复合物的共晶结构，开发了双重 Pim/DAPK3 抑制剂 (HS56) 和选择性 DAPK3 抑制剂（HS94 和 HS148），为高血压的多药理学提供机制见解。表明Pim激酶直接磷酸化平滑肌靶标，并且与选择性DAPK3抑制不同，Pim/DAPK3抑制显着降低收缩性。 在体内，HS56以剂量依赖性方式降低自发性高血压小鼠的血压，而不影响心率。这些发现表明，将 Pim 激酶抑制纳入高血压管理的多靶点参与策略中。HS56代表了分子靶向抗高血压药物开发的重要一步。
更新日期：2018-10-19
中文翻译：
靶向 Pim 激酶和 DAPK3 控制高血压
持续的血管平滑肌收缩过度会促进高血压和心血管疾病。收缩过度的病因尚不完全清楚。新的治疗靶点对于药物发现仍然至关重要。在这里，我们报道 Pim 激酶与 DAPK3 结合，调节收缩力并控制高血压。利用先导分子 (HS38) 与 DAPK3 复合物的共晶结构，开发了双重 Pim/DAPK3 抑制剂 (HS56) 和选择性 DAPK3 抑制剂（HS94 和 HS148），为高血压的多药理学提供机制见解。表明Pim激酶直接磷酸化平滑肌靶标，并且与选择性DAPK3抑制不同，Pim/DAPK3抑制显着降低收缩性。 在体内，HS56以剂量依赖性方式降低自发性高血压小鼠的血压，而不影响心率。这些发现表明，将 Pim 激酶抑制纳入高血压管理的多靶点参与策略中。HS56代表了分子靶向抗高血压药物开发的重要一步。
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