AUSTRALIAN JOURNAL OF BIOMEDICAL RESEARCH
Review Article
Sep 19, 2025 301 398

Beyond Inhibition: Emerging Small-Molecule Modalities in Oncology (Molecular Glues, Covalents, and Radiotheranostics)

Salvation Ifechukwude Atalor 1,
Aliaa Mohammed Mahmoud Soliman 2,
Oluwatobiloba Kehinde Adedokun 3,
Modinat Aina, Abayomi 4,
Cecilia Chika Unegbu 5,
Okoroafor Dorcas Okayo 6,
Victor Jonathan 7,
Kingsley Ugonna Ugoagwu 8,
Aliyu Olanrewaju Olaniyi 9 *
1 Department of Computer Science, Prairie View A&M University, Prairie View, TX, USA2 Department of Psychology and Counseling, Austin Peay State University, Clarksville, TN, USA3 Department of Surgery, General Hospital Odan, Lagos, Nigeria4 Department of Biology, Boston College, Chestnut Hill, MA, USA5 Department of Natural Sciences, Bowie State University, Jericho Park Rd, Bowie, MD, USA6 Department of Biomedical Technology, University of Port Harcourt, Port Harcourt, Nigeria7 Department of Chemistry, University of Washington, Seattle, WA, USA 8 Department of Immunology, College of Medicine, University of Ibadan, Ibadan, Nigeria9 Stockport NHS foundation trust, Stepping Hill Hospital, Stockport, Manchester, United Kingdom* Corresponding Author
Australian Journal of Biomedical Research, 1(2), 2025, aubm007, https://doi.org/10.63946/aubiomed/17089
Publication date: Sep 19, 2025
Full Text (PDF)

ABSTRACT

Background: Small-molecule drugs have transformed oncology, but conventional inhibitors are limited by resistance, restricted target scope, and declining durability.
Methods: We reviewed emerging small-molecule modalities—molecular glues, covalent inhibitors, and radiotheranostics—focusing on their mechanisms, clinical applications, and translational challenges. Key clinical trials and representative examples were identified from recent oncology literature.
Results: Molecular glues enable targeted degradation of previously undruggable proteins, with clinical success in multiple myeloma (IMiDs). Covalent inhibitors achieve durable suppression of oncogenic drivers such as KRAS^G12C and BTK, as shown in CodeBreaK100 (sotorasib; N=126; ORR 37%). Radiotheranostics combine imaging and therapy, exemplified by VISION (PSMA-617; N=831; OS HR 0.62) and NETTER-1 (Lutathera; N=229; PFS HR 0.21). Collectively, these modalities expand the druggable proteome, improve durability, and advance precision oncology.
Conclusion: Emerging small-molecule approaches mark a paradigm shift from inhibition alone to targeted degradation, durable covalent engagement, and diagnostic–therapeutic hybrids. Future priorities include improving selectivity, biomarker integration, scalable manufacturing, and equitable global access.

KEYWORDS

Molecular Glues Covalent Inhibitors Radiotheranostics Oncology Drug Discovery Targeted Protein Degradation Precision Oncology

CITATION (Vancouver)

Atalor SI, Soliman AMM, Adedokun OK, Abayomi MA, Unegbu CC, Okayo OD, et al. Beyond Inhibition: Emerging Small-Molecule Modalities in Oncology (Molecular Glues, Covalents, and Radiotheranostics). Australian Journal of Biomedical Research. 2025;1(2):aubm007. https://doi.org/10.63946/aubiomed/17089
APA
Atalor, S. I., Soliman, A. M. M., Adedokun, O. K., Abayomi, M. A., Unegbu, C. C., Okayo, O. D., Jonathan, V., Ugoagwu, K. U., & Olaniyi, A. O. (2025). Beyond Inhibition: Emerging Small-Molecule Modalities in Oncology (Molecular Glues, Covalents, and Radiotheranostics). Australian Journal of Biomedical Research, 1(2), aubm007. https://doi.org/10.63946/aubiomed/17089
Harvard
Atalor, S. I., Soliman, A. M. M., Adedokun, O. K., Abayomi, M. A., Unegbu, C. C., Okayo, O. D., . . . Olaniyi, A. O. (2025). Beyond Inhibition: Emerging Small-Molecule Modalities in Oncology (Molecular Glues, Covalents, and Radiotheranostics). Australian Journal of Biomedical Research, 1(2), aubm007. https://doi.org/10.63946/aubiomed/17089
AMA
Atalor SI, Soliman AMM, Adedokun OK, et al. Beyond Inhibition: Emerging Small-Molecule Modalities in Oncology (Molecular Glues, Covalents, and Radiotheranostics). Australian Journal of Biomedical Research. 2025;1(2), aubm007. https://doi.org/10.63946/aubiomed/17089
Chicago
Atalor, Salvation Ifechukwude, Aliaa Mohammed Mahmoud Soliman, Oluwatobiloba Kehinde Adedokun, Modinat Aina, Abayomi, Cecilia Chika Unegbu, Okoroafor Dorcas Okayo, Victor Jonathan, Kingsley Ugonna Ugoagwu, and Aliyu Olanrewaju Olaniyi. "Beyond Inhibition: Emerging Small-Molecule Modalities in Oncology (Molecular Glues, Covalents, and Radiotheranostics)". Australian Journal of Biomedical Research 2025 1 no. 2 (2025): aubm007. https://doi.org/10.63946/aubiomed/17089
MLA
Atalor, Salvation Ifechukwude et al. "Beyond Inhibition: Emerging Small-Molecule Modalities in Oncology (Molecular Glues, Covalents, and Radiotheranostics)". Australian Journal of Biomedical Research, vol. 1, no. 2, 2025, aubm007. https://doi.org/10.63946/aubiomed/17089

REFERENCES

  1. Baldi S, Long N, Ma S, Liu L, Al-Danakh A, Yang Q, et al. Advancements in Protein Kinase Inhibitors: From Discovery to Clinical Applications. Research (Wash D C). 2024;8:0747. doi: 10.34133/research.0747.
  2. Singh N, Vayer P, Tanwar S, Poyet JL, Tsaioun K, Villoutreix BO. Drug discovery and development: introduction to the general public and patient groups. Front Drug Discov [Internet]. 2023 May 24 [cited 2025 Aug 23];3. Available from: https://www.frontiersin.org/journals/drug-discovery/articles/10.3389/fddsv.2023.1201419/full
  3. Zhong G, Chang X, Xie W, Zhou X. Targeted protein degradation: advances in drug discovery and clinical practice. Sig Transduct Target Ther. 2024 Nov 6;9(1):308. doi: 10.1038/s41392-024-02011-0.
  4. Yadav RK, Ali A, Kumar S, Sharma A, Baghchi B, Singh P, et al. CAR T cell therapy: newer approaches to counter resistance and cost. Heliyon. 2020 Apr 16;6(4):e03779. doi: 10.1016/j.heliyon.2020.e03779.
  5. Qin S, Jiang J, Lu Y, Nice EC, Huang C, Zhang J, et al. Emerging role of tumor cell plasticity in modifying therapeutic response. Sig Transduct Target Ther. 2020 Oct 7;5(1):228. doi: 10.1038/s41392-020-00359-5.
  6. Huggins DJ, Sherman W, Tidor B. Rational Approaches to Improving Selectivity in Drug Design. J Med Chem. 2012 Feb 23;55(4):1424–44. doi: 10.1021/jm2010332.
  7. Fu YC, Liang SB, Luo M, Wang XP. Intratumoral heterogeneity and drug resistance in cancer. Cancer Cell International. 2025 Mar 18;25(1):103. doi: 10.1186/s12935-025-03468-9.
  8. Sasso JM, Tenchov R, Wang D, Johnson LS, Wang X, Zhou QA. Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic. Biochemistry. 2022 Jul 20;62(3):601. doi: 10.1021/acs.biochem.2c00246.
  9. Cheke RS, Kharkar PS. Covalent inhibitors: An ambitious approach for the discovery of newer oncotherapeutics. Drug Development Research. 2024;85(1):e22132. doi: 10.1002/ddr.22132.
  10. Herrmann K, Schwaiger M, Lewis JS, Solomon SB, McNeil BJ, Baumann M, et al. Radiotheranostics: a roadmap for future development. Lancet Oncol. 2020 Mar;21(3):e146–56. doi: 10.1016/S1470-2045(19)30821-6.
  11. Asatsuma-Okumura T, Ito T, Handa H. Molecular Mechanisms of the Teratogenic Effects of Thalidomide. Pharmaceuticals. 2020 May;13(5):95. doi: 10.3390/ph13050095.
  12. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins. Science. 2014 Jan 17;343(6168):305–9. doi: 10.1126/science.1244917.
  13. Yang Y, Li Z, Yang Y, Xiao P, He Z, Zhang Z, et al. The RBM39 degrader indisulam inhibits acute megakaryoblastic leukemia by altering the alternative splicing of ZMYND8. Cell Biosci. 2025 Apr 13;15(1):46. doi: 10.1186/s13578-025-01359-4.
  14. Shen Y, Wen W, Chen L, Zhang N, Cong W, Hu H. Recent Advances in Targeted Protein Degradation: Molecular Glues as Anticancer Drugs. Clin Exp Pharmacol Physiol. 2025 Sep;52(9):e70064. doi: 10.1111/1440-1681.70064.
  15. Baek K, Metivier RJ, Roy Burman SS, Bushman JW, Yoon H, Lumpkin RJ, et al. Unveiling the hidden interactome of CRBN molecular glues. Nat Commun. 2025 Jul 24;16(1):6831. doi: 10.1038/s41467-025-51200-4.
  16. Islam NN, Caulfield TR. Conditioned Generative Modeling of Molecular Glues: A Realistic AI Approach for Synthesizable Drug-like Molecules. Biomolecules. 2025 Jun;15(6):849. doi: 10.3390/biom15060849.
  17. Kim H, Hwang YS, Kim M, Park SB. Recent advances in the development of covalent inhibitors. RSC Med Chem. 2021;12(7):1037–45. doi: 10.1039/d1md00068c.
  18. Gai C, Harnor SJ, Zhang S, Cano C, Zhuang C, Zhao Q. Advanced approaches to developing targeted covalent drugs. RSC Med Chem. 2022;13(12):1460–75. doi: 10.1039/d2md00208c.
  19. Cox AD, Der CJ. “Undruggable KRAS”: druggable after all. Genes Dev. 2025 Jan 1;39(1–2):132–62. doi: 10.1101/gad.351764.125.
  20. Rozkiewicz D, Hermanowicz JM, Kwiatkowska I, Krupa A, Pawlak D. Bruton’s Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials. Molecules. 2023 Mar 6;28(5):2400. doi: 10.3390/molecules28052400.
  21. Grabe T, Jeyakumar K, Niggenaber J, Schulz T, Koska S, Kleinbölting S, et al. Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines. ACS Med Chem Lett. 2023 Apr 18;14(5):591–8. doi: 10.1021/acsmedchemlett.3c00017.
  22. McAulay K, Bilsland A, Bon M. Reactivity of Covalent Fragments and Their Role in Fragment-Based Drug Discovery. Pharmaceuticals (Basel). 2022 Nov 8;15(11):1366. doi: 10.3390/ph15111366.
  23. Kalgutkar AS, Dalvie DK. Drug discovery for a new generation of covalent drugs. Expert Opinion on Drug Discovery [Internet]. 2012 Jul 1 [cited 2025 Aug 23];7(7):561-81. Available from: https://www.tandfonline.com/doi/abs/10.1517/17460441.2012.688744 doi: 10.1517/17460441.2012.688744.
  24. Bodei L, Herrmann K, Schöder H, Scott AM, Lewis JS. Radiotheranostics in oncology: current challenges and emerging opportunities. Nat Rev Clin Oncol. 2022 Aug;19(8):534–50. doi: 10.1038/s41571-022-00652-y.
  25. Uemura M, Watabe T, Hoshi S, Tanji R, Yaginuma K, Kojima Y. The current status of prostate cancer treatment and PSMA theranostics. Ther Adv Med Oncol. 2023 Jul 3;15:17588359231182293. doi: 10.1177/17588359231182293.
  26. Advances With 225Ac-DOTATATE Targeted Alpha Therapy in Somatostatin Receptor Positive Neuroendocrine Tumors. Seminars in Nuclear Medicine [Internet]. 2025 Jul 4 [cited 2025 Aug 23]; Available from: https://www.sciencedirect.com/science/article/abs/pii/S0001299825000728 doi: 10.1053/j.semnuclmed.2025.04.006.
  27. Kalender E, Ekinci E, Elboğa U, Şahin E. Efficacy of 177Lu-PSMA-617 Therapy in mCRPC Patients with Liver Metastases: Insights into Survival Outcomes and Predictors of Response. Biomedicines. 2025 Feb 24;13(3):569. doi: 10.3390/biomedicines13030569.
  28. Santos S, Martins FA, P SA, Ferreira G, Lucena I. Treatment of lung neuroendocrine tumors with <SUP>177</SUP>Lu-DOTATATE: experience from a tertiary oncology centre. Endocrine Abstracts [Internet]. 2025 May 9 [cited 2025 Aug 23];110. Available from: https://www.endocrine-abstracts.org/ea/0110/ea0110p475
  29. Bednarz B. Theranostics and Patient-Specific Dosimetry. Semin Radiat Oncol. 2023 Jul;33(3):317–26. doi: 10.1016/j.semradonc.2023.03.007.
  30. Zhang S, Wang X, Gao X, Chen X, Li L, Li G, et al. Radiopharmaceuticals and their applications in medicine. Sig Transduct Target Ther. 2025 Jan 3;10(1):1. doi: 10.1038/s41392-024-01923-z.
  31. Dewey JA, Delalande C, Azizi SA, Lu V, Antonopoulos D, Babnigg G. Molecular Glue Discovery: Current and Future Approaches. J Med Chem. 2023 Jul 27;66(14):9278–96. doi: 10.1021/acs.jmedchem.3c00449.
  32. Jiang W, Ye W, Tan X, Bao YJ. Network-based multi-omics integrative analysis methods in drug discovery: a systematic review. BioData Min. 2025 Mar 28;18:27. doi: 10.1186/s13040-025-00403-6.
  33. Asatsuma-Okumura T, Ito T, Handa H. Molecular Mechanisms of the Teratogenic Effects of Thalidomide. Pharmaceuticals (Basel). 2020 May 13;13(5):95. doi: 10.3390/ph13050095.
  34. Wang Y, Chen D, Augusto R dos S, Liang J, Qin Z, Liu J, et al. Production Review of Accelerator-Based Medical Isotopes. Molecules. 2022 Aug 19;27(16):5294. doi: 10.3390/molecules27165294.
  35. Okafor CE, Egwuatu EC, Owosagba VA, Njei T, Adeyemi BI, Onuche PUO, et al. From Bench to Bedside: Medicinal Chemistry Strategies in the Development of Kinase Inhibitors for Cancer Therapy. Journal of Cancer and Tumor International. 2025 May 10;15(2):79–96. doi: 10.9734/jcti/2025/v15i2348.
  36. Bodaghi A, Fattahi N, Ramazani A. Biomarkers: Promising and valuable tools towards diagnosis, prognosis, and treatment of Covid-19 and other diseases. Heliyon. 2023 Jan 30;9(2):e13323. doi: 10.1016/j.heliyon.2023.e13323.
  37. Duran-Frigola M, Cigler M, Winter GE. Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence. J Am Chem Soc. 2023 Jan 27;145(5):2711–32. doi: 10.1021/jacs.2c11098.
  38. Onwuemelem LA, Orobator ET, Onyedum NN, Chibueze ES, Kanu I, Christopher AA, et al. Molecular Mechanisms of Clonal Hematopoiesis in Age-Related Cardiovascular Disease and Hematologic Malignancies: Review Article. Journal of Pharma Insights and Research. 2025 Apr 5;3(2):358–72. doi: 10.69613/jpir32.2025.358.
  39. Lawal OP, Orobator ET, Dorcas SI, Ezeamii VC, Foster-Pagaebi E, Attahiru M. Orphan Drug Development for Rare Diseases: Therapeutic Challenges, Translational Strategies, and Global Health Equity. Journal of Life Science and Public Health. 2025 Jun 30;1(1):1–9. doi: 10.69613/jlsph11.2025.1.

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