Studies of Materials with Physiological Properties

具有生理特性的材料的研究

• 批准号: 10424480
• 负责人: STUART L SCHREIBER
• 金额: $ 56.96万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424480
• 关键词: Adopted; Affinity; Award; Bar Codes; Binding; Biochemical; Biological; Biology; Cells; Collection; DNA; DNA sequencing; Dependence; Funding; Goals; Human; Human Biology; Human Genetics; Immunotherapy; Incubated; Libraries; Lipids; Measurement; Measures; Medicine; Messenger RNA; Methods; Modernization; National Institute of General Medical Sciences; Oligonucleotides; Pathway interactions; Phenotype; Physiological; Physiology; Property; Proteins; Public Health; Research; Research Personnel; Resistance; Strategic Planning; Synthesis Chemistry; Testing; Therapeutic; Time; Transcript; Translating; base; cancer cell; experimental study; functional genomics; insight; novel; novel therapeutics; precision medicine; small molecule; targeted treatment; transcriptome sequencing

The goal of the research in this Maximizing Investigators' Research Award (MIRA) is to develop transformative capabilities for discovering novel small molecules used to explore biology and advance medicine. The project aims to build on research enabled by 32 years of funding by NIGMS 038627 and 23 years of support by HHMI (ending Nov 2018). Although this research contributed to several important advances in biomedicine, it also revealed major gaps in our ability to translate insights from human biology into new medicines for public health. Overcoming these limitations is a primary aim of the proposed research. During the past five years of our GM038627-funded research, we used strategic planning principles of diversity-oriented synthesis (DOS) to synthesize a collection of novel, arrayed small molecules. Over 100 cell- based phenotypic screens were performed that yielded many novel small-molecule probes and candidates for novel therapeutics. We now propose to extend this use of modern, asymmetric synthesis to the discovery of compounds that bind target proteins. Discovering such `binders' remains a challenging first step towards developing compounds that confer specific activities on the target following binding – a key shortcoming in precision medicine guided by human genetics and functional genomics. To advance the discovery of small- molecule binders, we propose to pioneer diversity-oriented synthesis encoded by DNA oligonucleotides (DOSEDO) by synthesizing DNA bar-coded compounds resulting from DOS pathways. The resulting DNA- encoded libraries (DELs) will be incubated with tagged target proteins to affinity purify binders, which can be `decoded' using DNA sequencing. This project aims to meld advances in DOS with those of DELs, but benefitting simultaneously from the impressive advance of contemporary synthetic chemistry. A second key limitation has been the long time required to uncover the activities of newly synthesized small molecules. During the past five years, we introduced the concept of real-time annotation of small molecules, using cell painting to make > 1,000 cellular measurements of novel synthetic compounds within days of their synthesis. Our proposed research aims to develop an equally inexpensive and complementary method of real- time annotation – measuring compound-induced changes in the relative levels of thousands of cellular mRNA transcripts by bar-coding and pooling transcripts prior to a single RNA-Seq experiment (`HiTSeq'). Lastly, we will test the methods of DOSEDO, HiTSeq and others developed in the course of this MIRA by focusing on a cell state we recently showed to be adopted by cancer cells to confer resistance to chemothera- py, targeted therapeutics and immunotherapy. This lipophagy-induced, myofibroblastic cell state and its druggable vulnerability was discovered during the past five years of our GM038627-funded research. We will use this lipid-based pathway as a testing ground for new methods to discover small-molecule probes, to gain new biological insights, and to uncover novel dependencies that can be targeted with small molecules.

最大化研究者研究奖 (MIRA) 的研究目标是开发变革性的 发现用于探索生物学和推进医学的新型小分子的能力。项目 旨在以 NIGMS 038627 32 年的资助和 HHMI 23 年的支持为基础开展研究 （截至 2018 年 11 月）。尽管这项研究为生物医学领域的几项重要进展做出了贡献，但它也 揭示了我们将人类生物学的见解转化为公共卫生新药的能力方面的重大差距。 克服这些限制是拟议研究的主要目标。 在我们 GM038627 资助的研究的过去五年中，我们使用了以下战略规划原则： 面向多样性的合成（DOS），用于合成一系列新颖的、排列的小分子。超过100个细胞- 进行了基于表型的筛选，产生了许多新颖的小分子探针和候选物 新疗法。我们现在建议将现代不对称合成的用途扩展到发现 结合靶蛋白的化合物。发现这种“粘合剂”仍然是迈向目标的具有挑战性的第一步 开发在结合后赋予目标特定活性的化合物——这是该领域的一个关键缺点 以人类遗传学和功能基因组学为指导的精准医学。推进小分子物质的发现 分子结合剂，我们建议开创由 DNA 寡核苷酸编码的多样性导向合成 (DOSEDO) 通过合成 DOS 途径产生的 DNA 条形码化合物。由此产生的DNA—— 编码文库 (DEL) 将与标记的目标蛋白一起孵育，以亲和纯化结合物，这可以 使用 DNA 测序进行“解码”。该项目旨在将 DOS 的进步与 DEL 的进步融为一体，但是 同时受益于当代合成化学的令人印象深刻的进步。 第二个关键限制是发现新合成的小分子的活性需要很长时间。 分子。在过去的五年里，我们引入了小分子实时注释的概念， 使用细胞涂色在几天内对新型合成化合物进行超过 1,000 次细胞测量 合成。我们提出的研究旨在开发一种同样廉价且互补的方法 时间注释 – 测量化合物引起的数千个细胞 mRNA 相对水平的变化 在单个 RNA-Seq 实验（“HiTSeq”）之前，通过对转录本进行条形码编码和合并转录本。 最后，我们将测试 DOSEDO、HiTSeq 以及在本次 MIRA 过程中开发的其他方法： 重点关注我们最近证明癌细胞采用的一种细胞状态，以赋予对化疗的抵抗力 py，靶向治疗和免疫治疗。这种脂肪吞噬诱导的肌纤维母细胞状态及其 我们在过去五年的 GM038627 资助的研究中发现了可药物漏洞。我们将 使用这种基于脂质的途径作为发现小分子探针的新方法的试验场，以获得 新的生物学见解，并发现可以用小分子靶向的新依赖性。

项目成果

Synergistic Effects of Stereochemistry and Appendages on the Performance Diversity of a Collection of Synthetic Compounds.

• DOI: 10.1021/jacs.8b07319
• 发表时间: 2018-09-19
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Melillo B;Zoller J;Hua BK;Verho O;Borghs JC;Nelson SD Jr;Maetani M;Wawer MJ;Clemons PA;Schreiber SL
• 通讯作者: Schreiber SL

Modular Synthesis of Cyclopropane-Fused N-Heterocycles Enabled by Underexplored Diazo Reagents.

• DOI: 10.1002/anie.202203221
• 发表时间: 2022-09-19
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Richter, Matthieu J. R.;Zecri, Frederic J.;Briner, Karin;Schreiber, Stuart L.
• 通讯作者: Schreiber, Stuart L.

Diversity-oriented synthesis encoded by deoxyoligonucleotides.

• DOI: 10.1038/s41467-023-40575-5
• 发表时间: 2023-08-15
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Hudson L;Mason JW;Westphal MV;Richter MJR;Thielman JR;Hua BK;Gerry CJ;Xia G;Osswald HL;Knapp JM;Tan ZY;Kokkonda P;Tresco BIC;Liu S;Reidenbach AG;Lim KS;Poirier J;Capece J;Bonazzi S;Gampe CM;Smith NJ;Bradner JE;Coley CW;Clemons PA;Melillo B;Hon CS;Ottl J;Dumelin CE;Schaefer JV;Faust AME;Berst F;Schreiber SL;Zécri FJ;Briner K
• 通讯作者: Briner K

Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines.

• DOI: 10.1038/s41467-020-20478-5
• 发表时间: 2021-01-12
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Sharma M;Malhotra N;Yogavel M;Harlos K;Melillo B;Comer E;Gonse A;Parvez S;Mitasev B;Fang FG;Schreiber SL;Sharma A
• 通讯作者: Sharma A

Novel quaternary structures of the human prion protein globular domain.

• DOI: 10.1016/j.biochi.2021.09.005
• 发表时间: 2021-12
• 期刊: Biochimie
• 影响因子: 3.9
• 作者: Bortot LO;Rangel VL;Pavlovici FA;El Omari K;Wagner A;Brandao-Neto J;Talon R;von Delft F;Reidenbach AG;Vallabh SM;Minikel EV;Schreiber S;Nonato MC
• 通讯作者: Nonato MC