Developing an inhibitor of EIF2AK1 to overcome ineffective erythropoiesis in myelodysplastic syndromes with ringed sideroblasts

开发 EIF2AK1 抑制剂以克服环状铁粒幼细胞骨髓增生异常综合征中无效的红细胞生成

• 批准号: 10726479
• 负责人: Simona Colla
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726479
• 关键词: Affect; Anemia; Autophagocytosis; Biological; Biological Assay; Blood Transfusion; Bone Marrow; CD34 gene; CRISPR/Cas technology; Cancer Center; Cancer Science; Cell Culture System; Cell Line; Cells; Cellular Assay; Clinic; Deposition; Development; Dysmyelopoietic Syndromes; Engineering; Enzymes; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Eukaryotic Initiation Factors; Event; Future; Gene Expression; Genetic Transcription; Hematology; Hematopoietic; Hematopoietic stem cells; Heme; Hemoglobin; Impairment; In Vitro; Iron; Iron Overload; K-562; Malignant Neoplasms; Mitochondria; Molecular; Morphology; Mutation; Pathway interactions; Patients; Permeability; Phenotype; Phosphotransferases; Prokaryotic Initiation Factor-2; Protein Family; Protein Kinase; RNA Splicing; Recurrence; Risk; Sampling; Sickle Cell Anemia; Sideroblast; Signal Pathway; Signal Transduction; Spliced Genes; Testing; Therapeutic; Transforming Growth Factor beta; Transfusion; Translating; Validation; Vision; Work; adverse outcome; alternative treatment; cancer cell; candidate validation; cell type; clinical candidate; clinical development; clinical phenotype; cohort; effective therapy; engineered stem cells; erythroid differentiation; expectation; falls; genetically modified cells; heme biosynthesis; improved; improved outcome; induced pluripotent stem cell; inhibitor; insight; leukemic transformation; member; multidisciplinary; mutant; nanomolar; novel therapeutic intervention; novel therapeutics; peripheral blood; pharmacologic; progenitor; programs; response; side effect; single cell technology; small molecule; small molecule inhibitor; targeted treatment; therapeutic target; therapy development

ABSTRACT Mutations in the splicing factor SF3B1 (SF3B1MT), which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of MDS-RS, an MDS subtype characterized by the accumulation of ringed sideroblasts (RS) in the bone marrow. SF3B1MT are found in different hematopoietic cell types but preferentially deregulate erythroid progenitors. Although MDS-RS has a low propensity for leukemic transformation, most patients with MDS-RS have severe anemia and depend on regular blood transfusions despite the increased risk of iron overload and other adverse outcomes. The only agent approved for the treatment of transfusion-dependent MDS-RS patients who are ineligible for or have no response to erythropoiesis-stimulating agents is luspatercept, an inhibitor of TGFβ signaling. However, luspatercept has a response rate of less than 40%, which underscores the need for alternative treatment options that can alleviate impaired erythroid differentiation in these patients. In our previous study, we identified the EIF2AK1 response to heme deficiency as a potential driver of the SF3B1MT-induced arrest of erythroid differentiation. We therefore hypothesize that pharmacologically inhibiting EIF2AK1 activation overcomes ineffective erythropoiesis in patients with SF3B1-mutant MDS-RS. To test this hypothesis, we will pursue the specific aim of developing a small-molecule inhibitor of EIF2AK1 activity for proof-of-concept studies in SF3B1-mutant MDS samples. The findings of this aim will provide a direct line of sight to future compounds suitable for clinical development. We have partnered with the Institute of Applied Cancer Science at MD Anderson Cancer Center to develop small molecules targeting the EIF2AK1 pathway in MDS-RS. Our multidisciplinary team has already identified several EIF2AK1 inhibitors that have low nanomolar potency, are highly permeable and free of efflux, and have good selectivity relative to other members of the EIF2AK family of protein kinases. In the proposed work, we will functionally validate these candidates using cellular assays (employing primary cells, induced pluripotent stem cells, and genetically engineered cell lines) that we have developed over the last 3 years. If successful, this study will enable the development of the first inhibitor of EIF2AK1 activity. The proposed work has implications for the development of therapies to achieve long-lasting hematological responses in transfusion-dependent MDS-RS patients. Given that EIF2AK1 inhibition is one of the most promising therapeutic approaches for sickle cell anemia to date, the results of our work may have a broad spectrum of application.

抽象的 剪接因子 SF3B1 (SF3B1MT) 突变，发生在 20% 的骨髓增生异常患者中 综合征 (MDS) 是 MDS-RS 的标志，MDS-RS 是一种 MDS 亚型，其特征是累积 骨髓中的环状铁粒幼细胞（RS）。 SF3B1MT 存在于不同的造血细胞类型中，但 优先解除红系祖细胞的调节。尽管 MDS-RS 罹患白血病的可能性较低 大多数MDS-RS患者患有严重贫血并依赖定期输血 尽管铁过载和其他不良后果的风险增加。 唯一被批准用于治疗不符合输血依赖性 MDS-RS 患者的药物 对红细胞生成刺激剂有反应或没有反应的是 luspatercept，一种 TGFβ 信号传导抑制剂。 然而，luspatercept 的缓解率低于 40%，这凸显了替代药物的必要性 可以减轻这些患者红细胞分化受损的治疗方案。 在我们之前的研究中，我们发现 EIF2AK1 对血红素缺乏的反应是导致血红素缺乏的潜在驱动因素。 SF3B1MT 诱导的红细胞分化停滞。因此，我们假设药物抑制 EIF2AK1 激活克服了 SF3B1 突变 MDS-RS 患者无效的红细胞生成。为了测试这个 假设，我们将追求开发 EIF2AK1 活性的小分子抑制剂的具体目标 SF3B1 突变 MDS 样本的概念验证研究。这一目标的调查结果将提供一条直接路线 对适合临床开发的未来化合物的展望。 我们与 MD 安德森癌症中心应用癌症科学研究所合作开发 MDS-RS 中针对 EIF2AK1 通路的小分子。我们的多学科团队已经确定 几种 EIF2AK1 抑制剂具有低纳摩尔效力、高渗透性且无外排，并且具有 相对于 EIF2AK 蛋白激酶家族的其他成员，具有良好的选择性。在拟议的工作中，我们 将使用细胞测定（使用原代细胞、诱导多能细胞）对这些候选物进行功能验证 干细胞和基因工程细胞系）是我们在过去三年中开发的。如果成功的话， 这项研究将有助于开发第一个 EIF2AK1 活性抑制剂。 拟议的工作对开发实现持久血液学的疗法具有影响 输血依赖性 MDS-RS 患者的反应。鉴于 EIF2AK1 抑制是最重要的抑制之一 迄今为止，镰状细胞性贫血的治疗方法很有前景，我们的工作结果可能具有广泛的应用前景 应用范围。