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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目摘要父项目的主要目的是开发WDR5小分子降解器作为抗癌治疗。 WD40重复结构域蛋白5（WDR5），它起作用MLL组蛋白的必不可少的亚基甲基转移酶复合物对于基因转录法规至关重要，对于维持肿瘤生成至关重要在人类癌症中。在阿尔茨海默氏病（AD）中也暗示了WDR5，WDR5抑制剂是有效的在改善额叶皮层突触功能和AD小鼠中与内存相关的行为时。父项目不专注于广告。这种行政补充是为了回应特殊利益的通知，而不是 22-025，阿尔茨海默氏症以NIH赠款为重点的行政补品，而不是专注于阿尔茨海默氏症疾病。一些癌症患者还患有AD，这是一种毁灭性神经退行性疾病，目前没有有效的疾病修改疗法。 Synaptojanin 1（Synj1），主要磷酸肌醇双磷酸盐在大脑中降解酶并突触，在AD病理学中起着至关重要的作用。 Synj1表达增加活动与AD的认知下降和病理过程有关。 synj1也是在癌症中实施。它在各种癌症中过表达，而Synj1的高表达与较差癌症患者的预后。在我们的初步研究中，降低Synj1蛋白水平的化合物已经发现。降低Synj1降低化合物有效在几种AD鼠标模型中。在这个行政补充，我们建议进行一项领先优化运动，以生成优化的Synj1- 降低化合物提高效力，选择性和脑渗透。 Synj1降低化合物在此行政补充剂中产生的 AD的治疗，这也将使患有AD的癌症患者受益。这些降低的降低化合物也可能是有用的抗癌疗法。