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.

项目概要 母项目的主要目标是开发 WDR5 小分子降解剂作为抗癌药物 疗法。 WD40 重复结构域蛋白 5 (WDR5)，其功能是 MLL 组蛋白的重要亚基 甲基转移酶复合物对于基因转录调控至关重要，对于维持肿瘤发生至关重要 在人类癌症中。 WDR5 也与阿尔茨海默病 (AD) 有关，WDR5 抑制剂非常有效 改善 AD 小鼠前额皮质突触功能和记忆相关行为。父项目 不专注AD。本行政补充是为了回应特殊利益通知 NOT-AG- 22-025，针对不专注于阿尔茨海默氏症的 NIH 拨款的以阿尔茨海默氏症为重点的行政补充 疾病。一些癌症患者还患有 AD，这是一种毁灭性的神经退行性疾病，目前该疾病 没有有效的疾病缓解疗法。 Synaptojanin 1 (synj1)，主要的磷酸肌醇二磷酸 大脑和突触中的降解酶在 AD 病理学中起着至关重要的作用。 synj1 表达增加 和活动与认知能力下降和 AD 的病理过程有关。 Synj1 也是 与癌症有关。它在多种癌症中过度表达，并且 synj1 的高表达与低表达相关 癌症患者的预后。在我们的初步研究中，降低 synj1 蛋白水平的化合物已被 发现了。降低 synj1 的先导化合物是有效的 在几种 AD 小鼠模型中。在这个 行政补充，我们建议进行先导优化活动以生成优化的 synj1- 降低化合物 提高效力、选择性和大脑渗透性。降低 synj1 的化合物 该行政补充中产生的成果最终可以开发成有效的治疗方法 AD 的治疗，这也将使患有 AD 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。