Chemical Proteomic Platforms for Radically Expanding Cancer Druggability

用于从根本上扩展癌症成药性的化学蛋白质组学平台

• 批准号: 10693197
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 113.78万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693197
• 关键词: Acceleration; Basic Science; Biological Response Modifier Therapy; Biology; Cells; Chemicals; Code; DNA sequencing; Development; Future; Goals; Human; Human Genetics; Immune; Immunology; Immunooncology; Knowledge; Malignant Neoplasms; Maps; Medicine; Methods; Modernization; Molecular; Mutate; Natural Immunity; Oncogenes; Play; Proteins; Proteome; Proteomics; Research; Role; System; Technology; Therapeutic; Translating; Translational Research; Validation; activity-based protein profiling; adaptive immunity; anticancer research; biological systems; cancer cell; cancer therapy; gene discovery; genetic information; innovation; insight; novel therapeutics; pharmacologic; programs; protein degradation; small molecule; small molecule libraries; technological innovation; tumorigenesis; ubiquitin-protein ligase

Cancer research and treatment have greatly benefited from advances in DNA sequencing methods, which have accelerated the discovery of genes that, when mutated, promote tumorigenesis. The protein products of some of these oncogenes have served as direct targets for groundbreaking new medicines. Many oncogenes, however, code for proteins that lack chemical probes and are even considered undruggable. In these cases, our understanding of the molecular basis of cancer has not yet translated into effective new therapies. A similar gap can be found in cancer-related immunology (or immuno-oncology), where human genetics is discovering proteins that play fundamental roles in innate and adaptive immunity; yet, again, most of these proteins lack chemical probes. A critical challenge has thus emerged in cancer research – how can the massive gains in understanding of cancer and immunology bequeathed by modern human genetics be translated into new therapies for cancer? The goal of this research program is to leverage and extend our lab’s innovative activity- based protein profiling (ABPP) technology to radically expand the druggable content of the human proteome and develop high-quality chemical probes for genetically-defined protein targets in cancer and immuno- oncology. We have recently introduced advanced ABPP platforms that evaluate small-molecule interactions across thousands of proteins in parallel directly in native biological systems. By combining proteome-wide druggability maps of human cancer and immune cells furnished by ABPP with human genetic information, we have identified several high-priority cancer targets poised for chemical probe development. Optimized chemical probes will be used by our lab and a set of expert biology collaborators to characterize the functional relevance of protein targets in cancer and cancer-related immunology. We will also describe plans for continued technology innovation to further enhance chemical probe and target discovery by ABPP, including the following objectives – i) identify newly druggable E3 ligase systems capable of supporting targeted protein degradation in cancer cells; ii) discover chemical probes that selectively engage modified states of protein targets in cancer cells; and iii) generate advanced chemical libraries for ABPP to further increase the druggable fraction of the human cancer proteome. In summary, our research program should deliver high-quality chemical probes for, and pharmacological validation of, biologically compelling human cancer targets, providing critical knowledge to direct the future development of transformative cancer therapeutics. More generally, we envision that our research program will inspire chemical and cancer biologists to embrace the potential druggability of any human protein, as well as provide an experimental roadmap to realize this goal, for the benefit of both basic and translational research.

癌症研究和治疗极大地受益于DNA测序方法的进步

项目成果

Multiplexed proteomic profiling of cysteine reactivity and ligandability in human T cells.

• DOI: 10.1016/j.xpro.2021.100458
• 发表时间: 2021-06-18
• 期刊: STAR protocols
• 作者: Vinogradova EV;Cravatt BF
• 通讯作者: Cravatt BF

TMEM164 is an acyltransferase that forms ferroptotic C20:4 ether phospholipids.

• DOI: 10.1038/s41589-022-01253-7
• 发表时间: 2023-03
• 期刊: NATURE CHEMICAL BIOLOGY
• 影响因子: 14.8
• 作者: Reed, Alex;Ware, Timothy;Li, Haoxin;Bazan, J. Fernando;Cravatt, Benjamin F.
• 通讯作者: Cravatt, Benjamin F.

Chemoproteomics-Enabled Identification of 4-Oxo-β-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.

• DOI: 10.1002/anie.202210498
• 发表时间: 2022-11-21
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Carvalho, Luis A. R.;Ross, Breyan;Fehr, Lorenz;Bolgi, Oguz;Woehrle, Svenja;Lum, Kenneth M.;Podlesainski, David;Vieira, Andreia C.;Kiefersauer, Reiner;Felix, Rita;Rodrigues, Tiago;Lucas, Susana D.;Gross, Olaf;Geiss-Friedlander, Ruth;Cravatt, Benjamin F.;Huber, Robert;Kaiser, Markus;Moreira, Rui
• 通讯作者: Moreira, Rui

Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine.

• DOI: 10.1038/s41589-022-01098-0
• 发表时间: 2022-12
• 期刊: Nature chemical biology
• 影响因子: 14.8
• 作者: Kavanagh ME;Horning BD;Khattri R;Roy N;Lu JP;Whitby LR;Ye E;Brannon JC;Parker A;Chick JM;Eissler CL;Wong AJ;Rodriguez JL;Rodiles S;Masuda K;Teijaro JR;Simon GM;Patricelli MP;Cravatt BF
• 通讯作者: Cravatt BF

SPIN4 Is a Principal Endogenous Substrate of the E3 Ubiquitin Ligase DCAF16.

• DOI: 10.1021/acs.biochem.1c00067
• 发表时间: 2021-03-09
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Zhang X;Thielert M;Li H;Cravatt BF
• 通讯作者: Cravatt BF