Optimization of a Protein-Targeted Medicine into an RNA-Specific Small Molecule

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2023 Oct 23

PMID 37870980

Authors

Samantha M Meyer

Toru Tanaka

Amirhossein Taghavi

Jared T Baisden

Maison Grefe

Matthew D Disney

Affiliations

Soon will be listed here.

Abstract

Protein-targeted small molecule medicines often bind RNAs and affect RNA-mediated pathways in cells. Historically, small molecule engagement and modulation of RNA have not been considered in medicine development; however, RNA should be considered both a potential on- and off-target. Kinase inhibitors have emecrged as common RNA binders with dovitinib, a classic receptor tyrosine kinase (RTK) inhibitor, inhibiting RTKs and the biogenesis of oncogenic microRNA-21 through direct engagement. In this study, we use knowledge of the molecular recognition of both protein and RNA targets by dovitinib to design molecules that specifically inhibit the RNA target but lack activity against canonical protein targets in cells. As it is now becoming apparent that RNA can be both an on- and off-target for small molecule medicines, this study lays a foundation to use design principles to maximize desired compound activity while minimizing off-target effects.

Citing Articles

The evolution and application of RNA-focused small molecule libraries.

Taghavi A, Springer N, Zanon P, Li Y, Li C, Childs-Disney J RSC Chem Biol. 2025; .

PMID: 39957993 PMC: 11824871. DOI: 10.1039/d4cb00272e.

RNA binding proteins (RBPs) on genetic stability and diseases.

Aborode A, Abass O, Nasiru S, Eigbobo M, Nefishatu S, Idowu A Glob Med Genet. 2025; 12(1):100032.

PMID: 39925443 PMC: 11803229. DOI: 10.1016/j.gmg.2024.100032.

Technologies for Targeted RNA Degradation and Induced RNA Decay.

Mikutis S, Bernardes G Chem Rev. 2024; 124(23):13301-13330.

PMID: 39499674 PMC: 11638902. DOI: 10.1021/acs.chemrev.4c00472.

References

Butti R, Das S, Gunasekaran V, Yadav A, Kumar D, Kundu G . Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges. Mol Cancer. 2018; 17(1):34. PMC: 5817867. DOI: 10.1186/s12943-018-0797-x. View

Disney M . Targeting RNA with Small Molecules To Capture Opportunities at the Intersection of Chemistry, Biology, and Medicine. J Am Chem Soc. 2019; 141(17):6776-6790. PMC: 6541398. DOI: 10.1021/jacs.8b13419. View

Disney M, Winkelsas A, Pradeep Velagapudi S, Southern M, Fallahi M, Childs-Disney J . Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs. ACS Chem Biol. 2016; 11(6):1720-8. PMC: 4912454. DOI: 10.1021/acschembio.6b00001. View

Andre F, Bachelot T, Campone M, Dalenc F, Perez-Garcia J, Hurvitz S . Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res. 2013; 19(13):3693-702. DOI: 10.1158/1078-0432.CCR-13-0190. View

Warner K, Hajdin C, Weeks K . Principles for targeting RNA with drug-like small molecules. Nat Rev Drug Discov. 2018; 17(8):547-558. PMC: 6420209. DOI: 10.1038/nrd.2018.93. View

Arkin M, Wells J . Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov. 2004; 3(4):301-17. DOI: 10.1038/nrd1343. View

Klein T, Vajpai N, Phillips J, Davies G, Holdgate G, Phillips C . Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase. Nat Commun. 2015; 6:7877. PMC: 4525181. DOI: 10.1038/ncomms8877. View

Mayer M, James T . Detecting ligand binding to a small RNA target via saturation transfer difference NMR experiments in D(2)O and H(2)O. J Am Chem Soc. 2002; 124(45):13376-7. DOI: 10.1021/ja027526z. View

Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo Y . MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008; 18(3):350-9. DOI: 10.1038/cr.2008.24. View

10.

Tong Y, Gibaut Q, Rouse W, Childs-Disney J, Suresh B, Abegg D . . J Am Chem Soc. 2022; 144(26):11620-11625. PMC: 9594100. DOI: 10.1021/jacs.2c01929. View

11.

Janes J, Young M, Chen E, Rogers N, Burgstaller-Muehlbacher S, Hughes L . The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Proc Natl Acad Sci U S A. 2018; 115(42):10750-10755. PMC: 6196526. DOI: 10.1073/pnas.1810137115. View

12.

Zhang P, Liu X, Abegg D, Tanaka T, Tong Y, Benhamou R . Reprogramming of Protein-Targeted Small-Molecule Medicines to RNA by Ribonuclease Recruitment. J Am Chem Soc. 2021; 143(33):13044-13055. PMC: 9264281. DOI: 10.1021/jacs.1c02248. View

13.

Kommalapati A, Tella S, Borad M, Javle M, Mahipal A . FGFR Inhibitors in Oncology: Insight on the Management of Toxicities in Clinical Practice. Cancers (Basel). 2021; 13(12). PMC: 8231807. DOI: 10.3390/cancers13122968. View

14.

Ribeiro J, Rios-Vera C, Melo F, Schuller A . Calculation of accurate interatomic contact surface areas for the quantitative analysis of non-bonded molecular interactions. Bioinformatics. 2019; 35(18):3499-3501. PMC: 6748739. DOI: 10.1093/bioinformatics/btz062. View

15.

Bunney T, Wan S, Thiyagarajan N, Sutto L, Williams S, Ashford P . The Effect of Mutations on Drug Sensitivity and Kinase Activity of Fibroblast Growth Factor Receptors: A Combined Experimental and Theoretical Study. EBioMedicine. 2015; 2(3):194-204. PMC: 4471147. DOI: 10.1016/j.ebiom.2015.02.009. View

16.

Renhowe P, Pecchi S, Shafer C, Machajewski T, Jazan E, Taylor C . Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors. J Med Chem. 2008; 52(2):278-92. DOI: 10.1021/jm800790t. View

17.

Dalvit C, Fogliatto G, Stewart A, Veronesi M, Stockman B . WaterLOGSY as a method for primary NMR screening: practical aspects and range of applicability. J Biomol NMR. 2002; 21(4):349-59. DOI: 10.1023/a:1013302231549. View

18.

Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob S, Patel T . MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007; 133(2):647-58. PMC: 4285346. DOI: 10.1053/j.gastro.2007.05.022. View

19.

ODonnell K, Wentzel E, Zeller K, Dang C, Mendell J . c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005; 435(7043):839-43. DOI: 10.1038/nature03677. View

20.

Fang L, Velema W, Lee Y, Xiao L, Mohsen M, Kietrys A . Pervasive transcriptome interactions of protein-targeted drugs. Nat Chem. 2023; 15(10):1374-1383. DOI: 10.1038/s41557-023-01309-8. View