Characterizing the binding mechanisms of castration-resistant prostate cancer therapeutics to the intrinsically disordered N-terminal domain of the androgen receptor

表征去势抵抗性前列腺癌治疗药物与雄激素受体本质上无序的 N 端结构域的结合机制

• 批准号: 10656552
• 负责人: Paul Robustelli
• 金额: $ 40.96万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656552
• 关键词: Androgen Receptor; Antineoplastic Agents; Binding; Biological; Biophysics; Cellular Assay; Clinical; Clinical Trials; Development; Disease; Drug Design; Drug Targeting; Human; Laboratories; Measurement; Mediating; Methods; Molecular; Molecular Conformation; N-terminal; NMR Spectroscopy; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Physical condensation; Physiological; Proteins; Proteome; Research; Role; Structure; Therapeutic; Therapeutic Intervention; Work; castration resistant prostate cancer; drug candidate; experimental study; human disease; inhibitor; insight; novel; protein misfolding; rational design; simulation; small molecule; therapeutic target; three dimensional structure

Project Summary /Abstract Intrinsically disordered proteins (IDPs), which lack a fixed three-dimensional structure under physiological conditions, represent ~40% of the human proteome, have crucial functional roles in a variety of biological pathways and biomolecular assemblies and are implicated in a large number of human diseases. As IDPs populate a dynamic conformational ensemble of rapidly interconverting structures in solution, and cannot be represented by a single dominant conformation, or even a small number of substantially populated conformations, they are not suitable targets for conventional structure-based drug design methods. If it becomes possible to target IDPs with small molecule drugs, the druggable proteome will be dramatically expanded and therapeutic interventions may become accessible for currently untreatable diseases The PI’s laboratory utilizes an integrated computational and experimental research strategy to combine state-of-the-art all-atom molecular simulations with experimental measurements from NMR spectroscopy and other biophysical experiments to obtain atomistic descriptions of the dynamic binding mechanisms of IDPs and uses insights form these binding mechanisms to predict and rationally design novel binding interactions. This proposal focuses on applying this integrated computational and experimental approach to elucidate the binding mechanisms of small molecule drug candidates that target that intrinsically disordered domain of the androgen receptor and have entered clinical trials for castration resistant prostate cancer (CRPC). These binding mechanisms will be used to inform the rational design more potent and selective androgen receptor inhibitors and more effective CRPC therapeutics . This proposal describes a remarkable opportunity to draw connections between molecular binding mechanisms studied by molecular simulations and NMR, biological activity observed in cellular assays, and clinical results from human CRPC drug trials. This proposal will initiate a sustainable long-term research effort to combine computational and experimental methods to study the dynamic interactions of IDPs in a variety of cellular and pharmaceutical contexts. This research effort will stimulate the development of robust platforms to integrate computational and experimental methods that will dramatically increase the number of proteins amenable to structural and mechanistic characterization and pharmaceutical targeting and will provide new avenues to therapeutic interventions in diseases associated with aberrant biological interactions of IDPs such as those mediated by biomolecular condensate formation and protein misfolding.

项目摘要/摘要

项目成果

Molecular Basis of Small-Molecule Binding to α-Synuclein.

• DOI: 10.1021/jacs.1c07591
• 发表时间: 2022-02-16
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Robustelli P;Ibanez-de-Opakua A;Campbell-Bezat C;Giordanetto F;Becker S;Zweckstetter M;Pan AC;Shaw DE
• 通讯作者: Shaw DE

Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states.

靶向雄激素受体无序反式激活结构域的小分子会诱导崩溃的螺旋状态的形成。

• DOI: 10.1038/s41467-022-34077-z
• 发表时间: 2022-10-27
• 期刊: Nature communications
• 影响因子: 16.6

Rational optimization of a transcription factor activation domain inhibitor.

• DOI: 10.1038/s41594-023-01159-5
• 发表时间: 2023-12
• 期刊: NATURE STRUCTURAL & MOLECULAR BIOLOGY
• 影响因子: 16.8
• 作者: Basu, Shaon;Martinez-Cristobal, Paula;Frigole-Vivas, Marta;Pesarrodona, Mireia;Lewis, Michael;Szulc, Elzbieta;Banuelos, C. Adriana;Sanchez-Zarzalejo, Carolina;Bielskute, Stase;Zhu, Jiaqi;Pombo-Garcia, Karina;Garcia-Cabau, Carla;Zodi, Levente;Dockx, Hannes;Smak, Jordann;Kaur, Harpreet;Batlle, Cristina;Mateos, Borja;Biesaga, Mateusz;Escobedo, Albert;Bardia, Lidia;Verdaguer, Xavier;Ruffoni, Alessandro;Mawji, Nasrin R.;Wang, Jun;Obst, Jon K.;Tam, Teresa;Brun-Heath, Isabelle;Ventura, Salvador;Meierhofer, David;Garcia, Jesus;Robustelli, Paul;Stracker, Travis H.;Sadar, Marianne D.;Riera, Antoni;Hnisz, Denes;Salvatella, Xavier
• 通讯作者: Salvatella, Xavier