Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias

发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略

• 批准号: 10712396
• 负责人: Jian Jin
• 金额: $ 42.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712396
• 关键词: Acute Myelocytic Leukemia; Administrative Supplement; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Behavior; Binding; Brain; Calcium Channel; Calcium Channel Blockers; Cancer Patient; Cells; Complex; Dementia; Development; Disease; Enzymes; FDA approved; Future; Gene Expression Regulation; Genetic; Genetic Transcription; Grant; Human; Hypertension; Impaired cognition; In Vitro; Lead; Libraries; MLL gene; MLL-rearranged leukemia; Malignant Neoplasms; Mediating; Memory; Mus; Neurodegenerative Disorders; Nimodipine; Pancreatic Ductal Adenocarcinoma; Pathologic Processes; Penetration; Pharmaceutical Preparations; Plasma; Play; Preclinical Drug Development; Prefrontal Cortex; Prognosis; Proliferating; Property; Proteins; Reporting; Role; SYNJ1 gene; Senile Plaques; Solid Neoplasm; Structure-Activity Relationship; Synapses; Tertiary Protein Structure; Therapeutic; Transcriptional Regulation; United States National Institutes of Health; aging population; analog; anti-cancer therapeutic; blood-brain barrier penetration; c-myc Genes; cancer cell; cognitive function; design; efficacy study; histone methyltransferase; improved; in vivo; inhibitor; interest; lead optimization; malignant breast neoplasm; mouse model; novel; novel therapeutic intervention; overexpression; parent project; protein degradation; protein protein interaction; response; scaffold; screening; small molecule; synaptic function; therapeutically effective; tumorigenesis

PROJECT SUMMARY The main objective of the parent project is to develop WDR5 small-molecule degraders as anticancer therapeutics. WD40 repeat domain protein 5 (WDR5), which functions an essential subunit of the MLL histone methyltransferase complex, is critical for gene transcription regulations and essential for sustaining oncogenesis in human cancers. WDR5 is also implicated in Alzheimer’s Disease (AD), and WDR5 inhibitors are efficacious in improving prefrontal cortex synaptic function and memory-related behaviors in AD mice. The parent project does not focus on AD. This administrative supplement is in response to the Notice of Special Interest NOT-AG- 22-025, Alzheimer’s-Focused Administrative Supplements for NIH Grants that are Not Focused on Alzheimer’s Disease. Some cancer patients also suffer from AD, a devastating neurodegenerative disorder, which currently has no effective disease-modifying therapeutics. Synaptojanin 1 (synj1), the main phosphoinositol bisphosphate degrading enzyme in the brain and synapses, plays a critical role in AD pathology. Increased synj1 expression and activities have been associated with cognitive decline and pathological processes of AD. Synj1 is also implicated in cancer. It is overexpressed in various cancers, and high expression of synj1 correlates with poor prognosis in cancer patients. In our preliminary studies, compounds that lower the synj1 protein level have been discovered. The lead synj1-lowering compounds were efficacious in several AD mouse models. In this administrative supplement, we propose to conduct a lead optimization campaign to generate optimized synj1- lowering compounds with improved potency, selectivity and brain penetration. The synj1-lowering compounds generated in this administrative supplement could ultimately be developed into effective therapeutics for the treatment of AD, which will also benefit cancer patients who suffer from AD. These synj1-lowering compounds could also be useful anticancer therapeutics.

项目总结 母项目的主要目标是开发WDR5小分子降解剂作为抗癌药物 治疗学。WD40重复结构域蛋白5(WDR5)，其功能是MLL组蛋白的一个重要亚基 甲基转移酶复合体是基因转录调控的关键，也是维持肿瘤发生的关键 在人类癌症中。WDR5也与阿尔茨海默病(AD)有关，WDR5抑制剂是有效的 改善阿尔茨海默病小鼠前额叶皮质突触功能和记忆相关行为。父项目 不专注于AD。本行政副刊是对NOT-AG-特殊利益通知的回应 22-025，针对非阿尔茨海默氏症的NIH补助金的阿尔茨海默氏症行政补充 疾病。一些癌症患者还患有阿尔茨海默病，这是一种毁灭性的神经退行性疾病，目前 没有有效的治疗疾病的方法。Synaptojanin 1(Synj1)，主要的二磷酸肌醇 脑和突触中的降解酶在AD的病理过程中起着关键作用。Synj1表达增加 活动与阿尔茨海默病的认知功能下降和病理过程有关。Synj1也是 与癌症有关。它在多种肿瘤中高表达，高表达与差相关 癌症患者的预后。在我们的初步研究中，降低synj1蛋白水平的化合物 被发现了。降铅化合物是有效的。 在几个AD小鼠模型中。在这 行政补充，我们建议开展一项领先的优化活动，以生成优化的synj1- 用来降低复合词 提高了效力、选择性和脑渗透率。降低Synj1的化合物 在本行政副刊中产生的结果最终可能被开发成治疗 治疗阿尔茨海默病，这也将使患有阿尔茨海默病的癌症患者受益。这些降低synj1的化合物 也可能是有用的抗癌疗法。