Small Molecule NOTCH Inhibitors for the treatment of pulmonary hypertension

 描述（由申请人提供）：肺动脉高压（PH）是一种无法治愈的疾病，其特征是小肺动脉和小动脉逐渐狭窄，导致生活质量大幅下降，长期发病率和死亡率显著增加。有5类PH被WHO认可，包括肺动脉高压（PAH，1.1类）和低氧血症诱导的PH（3类），我们的数据表明NOTCH 3在这两种疾病的血管平滑肌（vSMC）发病机制中。具体而言，NOTCH 3介导PH的两种基本表现：小肺动脉平滑肌细胞的过度增殖和由缺氧诱导的过度钙库操纵的钙内流（SOCE），其分别是血管重塑和血管收缩性疾病表型的基础。为了推进NOTCH抑制将是治疗性的假设，我们开发了NOTCH与其转录效应子RBPJ之间相互作用的高度有效和选择性的小分子抑制剂。合乎逻辑的下一步是测试新的NOTCH抑制剂逆转PH症状的能力，使用动物模型在体内和在血管平滑肌细胞的原代培养物中来自人的小肺动脉和小动脉在体外。认识到没有单一的动物模型再现人类的状况，包括性别选择性和发病机制，我们将使用三种啮齿动物模型，我们假设血管收缩和过度增殖的细胞表型由NOTCH/RBPJ调节。具体目标是：1）开发NOTCH：RBPJ的选择性小分子抑制剂以探测PH中的功能2）使用患者来源的小肺动脉平滑肌细胞（sPASMC）测试新型抑制剂是否阻断PH表型。3)评价抑制RBPJ是否逆转动物模型中的PH血管病变。总之，该多PI/PD提案建立在我们互补的专业知识基础上，以检验NOTCH/RBPJ的药理学抑制可用于成功治疗PH的假设，PH是一种具有挑战性且通常无法治愈的疾病。该项目非常重要，因为它靶向了一种似乎是多种形式PH病理基础的途径。它具有高度创新性，因为它促进了新一代选择性小分子NOTCH抑制剂的开发，以治疗PH。

 DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is largely incurable disease characterized by a narrowing of the small pulmonary arteries and arterioles that progressively worsens, causing substantial loss of quality of life, and significant long-term morbidity and mortality. There are 5 classes of PH recognized by the WHO, including pulmonary arterial hypertension (PAH, Class 1.1) and hypoxemia-induced PH (Class 3) for which our data implicate NOTCH3 in the vascular smooth muscle (vSMC) pathogenesis of both of these types of disease. Specifically, NOTCH3 mediates two fundamental manifestations of PH: hyperproliferation of small pulmonary artery smooth muscle cells and the excessive store-operated calcium entry (SOCE) induced by hypoxia that underlie vascular remodeling and vasoconstrictive disease phenotypes, respectively. To advance the hypothesis that NOTCH inhibition would be therapeutic, we developed highly potent and selective small molecule inhibitors of the interaction between NOTCH and its transcriptional effector RBPJ. A logical next step is to test the new NOTCH inhibitors for the ability to reverse PH symptoms using animal models in vivo and in primary cultures of vascular smooth muscle cells derived from the human small pulmonary arteries and arterioles in vitro. Recognizing that no single animal model reproduces the human condition, including gender selectivity and pathogenesis, we will use three rodent models that present the vasoconstrictive and hyperproliferative cellular phenotypes we postulate are regulated by NOTCH/RBPJ. The Specific Aims are: 1) Develop selective small molecule inhibitors of NOTCH:RBPJ to probe function in PH 2) Test whether the novel inhibitors block PH phenotypes using patient-derived small pulmonary artery smooth muscle cells (sPASMCs). 3) Evaluate whether inhibiting RBPJ reverses PH vasculopathy in animal models. In summary, this multi-PI/PD proposal builds on our complementary expertise to test the hypothesis that pharmacological inhibition of NOTCH/RBPJ can be used to successfully treat PH, which is a challenging and often incurable disease. The project is highly significant since it targets a pathway that appears to underlie pathology in multiple forms of PH. It is highly innovative since it advances the development of a new generation of selective small molecule inhibitors of NOTCH to treat PH.