Small Molecules Targeting the Disordered Transactivation Domain of the Androgen Receptor Induce the Formation of Collapsed Helical States

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Oct 27

PMID 36302916

Authors

Jiaqi Zhu

Xavier Salvatella

Paul Robustelli

Affiliations

Soon will be listed here.

Abstract

Intrinsically disordered proteins, which do not adopt well-defined structures under physiological conditions, are implicated in many human diseases. Small molecules that target the disordered transactivation domain of the androgen receptor have entered human trials for the treatment of castration-resistant prostate cancer (CRPC), but no structural or mechanistic rationale exists to explain their inhibition mechanisms or relative potencies. Here, we utilize all-atom molecular dynamics computer simulations to elucidate atomically detailed binding mechanisms of the compounds EPI-002 and EPI-7170 to the androgen receptor. Our simulations reveal that both compounds bind at the interface of two transiently helical regions and induce the formation of partially folded collapsed helical states. We find that EPI-7170 binds androgen receptor more tightly than EPI-002 and we identify a network of intermolecular interactions that drives higher affinity binding. Our results suggest strategies for developing more potent androgen receptor inhibitors and general strategies for disordered protein drug design.

Citing Articles

The androgen receptor amino-terminal domain: structure, function and therapeutic potential.

Hunter I, Jamieson C, McEwan I Endocr Oncol. 2025; 5(1):e240061.

PMID: 40051657 PMC: 11883864. DOI: 10.1530/EO-24-0061.

Ensemble docking for intrinsically disordered proteins.

Dhar A, Sisk T, Robustelli P bioRxiv. 2025; .

PMID: 39896485 PMC: 11785235. DOI: 10.1101/2025.01.23.634614.

Proximity-enhanced cysteine-histidine crosslinking for elucidating intrinsically disordered and other protein complexes.

Wu Q, van den Wildenberg S, Brzoskowski J, van den Oetelaar M, Verhoef C, Genet S Chem Sci. 2025; 16(8):3523-3535.

PMID: 39850253 PMC: 11752056. DOI: 10.1039/d4sc07419j.

Ion mobility mass spectrometry unveils conformational effects of drug lead EPI-001 on the intrinsically disordered N-terminal domain of the androgen receptor.

Ahmed I, Rofe A, Henry M, West E, Jamieson C, McEwan I Protein Sci. 2024; 34(1):e5254.

PMID: 39665260 PMC: 11635395. DOI: 10.1002/pro.5254.

Covalent adducts formed by the androgen receptor transactivation domain and small molecule drugs remain disordered.

Zhu J, Robustelli P bioRxiv. 2024; .

PMID: 39605539 PMC: 11601358. DOI: 10.1101/2024.11.12.623257.

References

van der Lee R, Buljan M, Lang B, Weatheritt R, Daughdrill G, Dunker A . Classification of intrinsically disordered regions and proteins. Chem Rev. 2014; 114(13):6589-631. PMC: 4095912. DOI: 10.1021/cr400525m. View

Habchi J, Tompa P, Longhi S, Uversky V . Introducing protein intrinsic disorder. Chem Rev. 2014; 114(13):6561-88. DOI: 10.1021/cr400514h. View

Tompa P . Intrinsically unstructured proteins. Trends Biochem Sci. 2002; 27(10):527-33. DOI: 10.1016/s0968-0004(02)02169-2. View

Dunker A, Cortese M, Romero P, Iakoucheva L, Uversky V . Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J. 2005; 272(20):5129-48. DOI: 10.1111/j.1742-4658.2005.04948.x. View

Dyson H, Wright P . Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol. 2005; 6(3):197-208. DOI: 10.1038/nrm1589. View

Wright P, Dyson H . Intrinsically disordered proteins in cellular signalling and regulation. Nat Rev Mol Cell Biol. 2014; 16(1):18-29. PMC: 4405151. DOI: 10.1038/nrm3920. View

Sormanni P, Piovesan D, Heller G, Bonomi M, Kukic P, Camilloni C . Simultaneous quantification of protein order and disorder. Nat Chem Biol. 2017; 13(4):339-342. DOI: 10.1038/nchembio.2331. View

Banani S, Lee H, Hyman A, Rosen M . Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol. 2017; 18(5):285-298. PMC: 7434221. DOI: 10.1038/nrm.2017.7. View

Babu M, van der Lee R, Sanchez de Groot N, Gsponer J . Intrinsically disordered proteins: regulation and disease. Curr Opin Struct Biol. 2011; 21(3):432-40. DOI: 10.1016/j.sbi.2011.03.011. View

10.

Heller G, Sormanni P, Vendruscolo M . Targeting disordered proteins with small molecules using entropy. Trends Biochem Sci. 2015; 40(9):491-6. DOI: 10.1016/j.tibs.2015.07.004. View

11.

Heller G, Bonomi M, Vendruscolo M . Structural Ensemble Modulation upon Small-Molecule Binding to Disordered Proteins. J Mol Biol. 2018; 430(16):2288-2292. DOI: 10.1016/j.jmb.2018.03.015. View

12.

Sadar M . Discovery of drugs that directly target the intrinsically disordered region of the androgen receptor. Expert Opin Drug Discov. 2020; 15(5):551-560. PMC: 8693730. DOI: 10.1080/17460441.2020.1732920. View

13.

Cournia Z, Allen B, Sherman W . Relative Binding Free Energy Calculations in Drug Discovery: Recent Advances and Practical Considerations. J Chem Inf Model. 2017; 57(12):2911-2937. DOI: 10.1021/acs.jcim.7b00564. View

14.

Jensen M, Ruigrok R, Blackledge M . Describing intrinsically disordered proteins at atomic resolution by NMR. Curr Opin Struct Biol. 2013; 23(3):426-35. DOI: 10.1016/j.sbi.2013.02.007. View

15.

Lee H, Mok K, Muhandiram R, Park K, Suk J, Kim D . Local structural elements in the mostly unstructured transcriptional activation domain of human p53. J Biol Chem. 2000; 275(38):29426-32. DOI: 10.1074/jbc.M003107200. View

16.

Biesaga M, Frigole-Vivas M, Salvatella X . Intrinsically disordered proteins and biomolecular condensates as drug targets. Curr Opin Chem Biol. 2021; 62:90-100. PMC: 7616887. DOI: 10.1016/j.cbpa.2021.02.009. View

17.

Michaels T, Saric A, Meisl G, Heller G, Curk S, Arosio P . Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors. Proc Natl Acad Sci U S A. 2020; 117(39):24251-24257. PMC: 7533883. DOI: 10.1073/pnas.2006684117. View

18.

Wojcik S, Birol M, Rhoades E, Miranker A, Levine Z . Targeting the Intrinsically Disordered Proteome Using Small-Molecule Ligands. Methods Enzymol. 2018; 611:703-734. DOI: 10.1016/bs.mie.2018.09.036. View

19.

Doig A, Derreumaux P . Inhibition of protein aggregation and amyloid formation by small molecules. Curr Opin Struct Biol. 2015; 30:50-56. DOI: 10.1016/j.sbi.2014.12.004. View

20.

De Mol E, Fenwick R, Phang C, Buzon V, Szulc E, de la Fuente A . EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor. ACS Chem Biol. 2016; 11(9):2499-505. PMC: 5027137. DOI: 10.1021/acschembio.6b00182. View