Recent Update on Development of Small-Molecule STAT3 Inhibitors for Cancer Therapy: From Phosphorylation Inhibition to Protein Degradation

STATs in cancer inflammation and immunity: a leading role for STAT3

Yu, H., Pardoll, D., & Jove, R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2734 · Cited by 4,383

STATs and Gene Regulation

Darnell, J. E. (1997) · Science · doi:10.1126/science.277.5332.1630 · Cited by 3,979

Revisiting STAT3 signalling in cancer: new and unexpected biological functions

Yu, H., Lee, H., Herrmann, A., Buettner, R., & Jove, R. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3818 · Cited by 2,137

Induced protein degradation: an emerging drug discovery paradigm

Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486

Indoleamine 2,3-dioxygenase and tumor-induced tolerance

Munn, D. H., & Mellor, A. L. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31178 · Cited by 1,093

Stat3 Dimerization Regulated by Reversible Acetylation of a Single Lysine Residue

Yuan, Z.-L., Guan, Y.-J., Chatterjee, D., & Chin, Y. E. (2005) · Science · doi:10.1126/science.1105166 · Cited by 790

Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity

Siddiquee, K., Zhang, S., Guida, W. C., Blaskovich, M. A., Greedy, B. M., Lawrence, H. R., Yip, M. L. R., Jove, R., McLaughlin, M. M., Lawrence, N. J., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609757104 · Cited by 741

Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

Marzec, M., Zhang, Q., Goradia, A., Raghunath, P. N., Liu, X., Paessler, M. E., Wang, H. Y., Wysocka, M., Cheng, M. M., Ruggeri, B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810958105 · Cited by 731

A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

Bai, L., Zhou, H., Xu, R., Zhao, Y., Chinnaswamy, K., McEachern, D., Chen, J., Yang, C.-Y., Liu, Z., Wang, M., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.10.002 · Cited by 652

Synthesis, characterization, structural analysis and cytotoxic evaluation of novel pyrrolidin-2-one tethered 1,3,4-oxadiazole hybrids

S, M. Y. H., Kempasiddegowda, M. S., Ravi, B. B., Preetham, H. D., Swaroop, T. R., Naveen, S., Lokanath, N. K., Rangappa, K. S., & Basappa, B. (2026) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2026.146401

Piperlongumine inhibits the proliferation and migration of non-small cell lung cancer cells through the EGFR/FAK/STAT3 pathway

Huang, Q., Chen, W., Xu, X., Hua, J., Li, L., Hu, P., Zhang, W., & Sun, L. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-11943-3

Nanomedicine strategies targeting STAT3 in cancer: From tumor suppression to microenvironment modulation

Chama, Z., Yousif, A. Y., Patel, P. N., Singh, G., Arora, V., Baig, M. R., Abohassan, M., Nayak, P. P., Iqbal, M. S., & Basunduwah, T. S. (2026) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/j.jpet.2026.104954

Design and synthesis of 1-Phenyl-2-thioaryl-4-benzyl-5-methylimidazoles as dual STAT3/NF-κB inhibitors for triple-negative breast Cancer therapy

Abdellatef, A. A., Al-Kubeisi, A. K., Fahmy, S. M., Georghiou, P. E., Loksha, Y. M., Hayakawa, Y., Beshay, B. Y., & Bekhit, A. A. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110084

Alternative splicing mechanisms contributing to cold adaptation in the Amur sleeper (Perccottus glenii)

Lu, H., Li, W., Zhu, Z., Hu, P., Chen, L., & Xu, Q. (2026) · Hydrobiologia · doi:10.1007/s10750-026-06265-1

Discovery of novel NQO1/STAT3/HDAC triple-target agents for the treatment of triple negative breast cancer

Li, S., Ma, D., Han, Z., Zhang, C., & Wu, L. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110146

Andrographolide inhibits hepatocellular carcinoma progression and programmed death ligand-1 expression by blocking STAT3 phosphorylation

Fu, H., Yuan, Y., Tan, J., Pang, Y., & Long, Y. (2026) · Indian Journal of Pharmacology · doi:10.4103/ijp.ijp_860_25

MiR-184-3p suppressed atherosclerosis in ApoE-/- mice via inhibiting STAT3/IL-6/IL-1β/TNFα signaling induced inflammation and apoptosis

Jia, Q., Chen, F., Wang, J., Li, W., Guangxia, L. I. U., Cao, G., & zhai, J. (2026) · European journal of medical research · doi:10.1186/s40001-026-04799-7

A Derivative of Plumbagin Targets the JAK2/STAT3 Pathway to Inhibit the Progression of Oral Squamous Cell Carcinoma

Sun, X., He, Y., Xiao, T., Dong, Y., Tian, J., Wang, K., Ma, H., Wang, Z., Zhou, H., Wang, Q., et al. (2026) · Molecules · doi:10.3390/molecules31142419

Discovery of SH-17 as a pioneering STAT3/HDAC bifunctional inhibitor that simultaneously impairs Tyr705 and Ser727 phosphorylation

Liu, Y., Gao, X., Xu, W., Zhang, Y., Jiang, X., Ma, X., & Wang, Y. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110243

Melatonin hybrids as multifunctional therapeutic agents: A comprehensive review

Damirchi, E. K., Barani, A., Hamidi, S. M., & Ebrahimzadeh, M. A. (2026) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2026.119156

Targeting Cys328 in the STAT3 DNA-binding domain with the germacrane-type sesquiterpene lactone SCP-7 inhibits colorectal Cancer growth in vitro and in vivo

Li, Y., Zhang, G., Wang, Y., Ma, W., 国海东, Ding, Z., Xian, Y., Liu, Q., Yao, G., & Song, S. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110273

Fluorinated Chromone Derivatives: Synthesis, Theoretical Study, and Evaluation of Their Biological Potential

Heredia‐Moya, J., Fiallos-Ayala, A., Zúñiga-Miranda, J., González‐Pastor, R., Viteri, A., Cevallos‐Morillo, C. A., Romero-Benavides, J. C., & Alcívar-León, C. D. (2026) · ACS Omega · doi:10.1021/acsomega.6c03643

Development of thiazole-hydrazone hybrids for targeted therapy of non-small cell lung cancer

Altıntop, M. D., Ertorun, İ., Çiftçi, G. A., & Özdemır, A. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110369

Toxoplasma gondii infection reduces CD59 expression through downregulation of JAK2/STAT3 signaling axis to enhance decidual NK cell cytotoxicity via the RAS/MAPK pathway

Wang, S., Huo, L., Zou, Y., Yang, R., Wang, X., Zhang, H., Ren, L., Yang, J., Li, J., Hu, X., et al. (2026) · Inflammation Research · doi:10.1007/s00011-026-02344-0

Dual-target carbonic anhydrase inhibitors in cancer therapy: progress, challenges, and opportunities

Luo, M., Wang, Y., Xia, Y., Qin-min, W., Zhang, J., & Shan, L. (2026) · Medicinal Chemistry Research · doi:10.1007/s00044-026-03605-7

NR4A3 mediates Coal Dust Nanoparticle-induced Immunopathogenesis in Rheumatoid ArthritisPreprint

Zhang, Y., Jia, L., Wang, J., Zhang, Y., Qian, X., He, X., Ma, Y., Zhang, C., Qian, Q., Zai, Z., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-10711979/v1

Discovery of β-carboline derivatives as potent STAT3 dual phosphorylation inhibitor for hepatocellular carcinoma treatment

Jian, Z., Wei, L., Ren, M., Zhou, Z., Zhu, Z., Wei, J., Huang, R., 许艳丽, Zhang, Y., & Chen, Y. (2026) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2026.119276

Synthesis and Biological Evaluation of a New Family of STAT3 Inhibitors by a Diversity Oriented Approach Based on the Ugi-Multicomponent Reaction

Lambruschini, C., Anselmo, M., Banfi, L., Bertola, N., Carbotti, G., Cavalluzzi, M. M., Lentini, G., Rocca, V. M., Rosano, C., Viale, M., et al. (2026) · ACS Omega · doi:10.1021/acsomega.6c07733

Chlorinated chaetoviridin-type azaphilones discovered via metabolomics: structural diversity and suppression of STAT3 signaling in gastric cancer cells

Wang, W., Zheng, L., Luo, L., Huang, Z., Zhang, B., Fu, X.-T., Li, Y., Xia, J., & Shao, Z. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110524

Design, synthesis and biological evaluation of novel Brevilin A derivatives as antitumor agents

Wen, L.-X., Liu, A., Li, J., Zhan, R., Qi, X.-K., & Huang, H. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110534

20(S)-Ginsenoside Rh2 Promotes Apoptotic and Autophagic Cell Death in Melanoma Cells by Inhibiting Src/STAT3 Signaling Pathway

Osei, D., Afriyie, A., & Adu, K. (2024) · Specialty journal of Pharmacognosy Phytochemistry and Biotechnology · doi:10.51847/8rknqxtggj

Protein degraders targeting JAK/STAT3 signaling pathway are emerging therapeutic modalities for human cancers

Feng, X., Li, N., Chen, X., Cao, X., Dai, J., Xiong, S., & Yuan, Z. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118532

Cardiomyocyte-enriched OTUD5 alleviates pathological myocardial hypertrophy by deubiquitinating STAT3 and modulating the STAT3–PGC-1α axis

Ye, B., Jiang, Y., Zheng, Z., Jin, Y., Liao, Y., Jia, Z., Lin, W., Xu, D., Han, J., Fang, Z., et al. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-026-01870-5

BindingDB Entry 50023007: Discovery of SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression.

BindingDB (2026) · UC San Diego · doi:10.7270/q29g5spm

BindingDB Entry 50015680: Discovery of a Highly Potent and Orally Bioavailable STAT3 Dual Phosphorylation Inhibitor for Pancreatic Cancer Treatment.

BindingDB (2023) · UC San Diego · doi:10.7270/q2rb78j1

BindingDB Entry 50021879: Research progress of multi-target HDAC inhibitors blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway in the treatment of cancer.

BindingDB (2025) · UC San Diego · doi:10.7270/q2gh9pnb

BindingDB Entry 50022220: Natural Product-Inspired Discovery of Naphthoquinone-Furo-Piperidine Derivatives as Novel STAT3 Inhibitors for the Treatment of Triple-Negative Breast Cancer.

BindingDB (2025) · UC San Diego · doi:10.7270/q2rj4q6v

BindingDB Entry 50015981: Discovery of a Novel Potent STAT3 Inhibitor HP590 with Dual p-Tyr

BindingDB (2023) · UC San Diego · doi:10.7270/q2rf6006

BindingDB Entry 50023603: Challenging the "Undruggable"─Targeting STAT3 but Identifying Potent TrkA-Targeted Inhibitors.

BindingDB (2026) · UC San Diego · doi:10.7270/q2bk1j9m

BindingDB Entry 50021398: Bipyridine Derivatives as NOP2/Sun RNA Methyltransferase 3 Inhibitors for the Treatment of Colorectal Cancer.

BindingDB (2025) · UC San Diego · doi:10.7270/q2cr600w

BindingDB Entry 50018020: Boronic Acid: A Novel Pharmacophore Targeting Src Homology 2 (SH2) Domain of STAT3.

BindingDB (2023) · UC San Diego · doi:10.7270/q2h9999j

BindingDB Entry 50023126: Discovery of naphthoquinone-furo-piperidone derivatives as dual targeting agents of STAT3 and NQO1 for the treatment of breast cancer.

BindingDB (2026) · UC San Diego · doi:10.7270/q2fn1c3g

BindingDB Entry 50019392: Research progress of STAT3-based dual inhibitors for cancer therapy.

BindingDB (2024) · UC San Diego · doi:10.7270/q2tm7ghf

BindingDB Entry 50015942: S3I-201 derivative incorporating naphthoquinone unit as effective STAT3 inhibitors: Design, synthesis and anti-gastric cancer evaluation.

BindingDB (2023) · UC San Diego · doi:10.7270/q2pn99mk

BindingDB Entry 50023362: STATs, promising targets for the treatment of autoimmune and inflammatory diseases.

BindingDB (2026) · UC San Diego · doi:10.7270/q2p2742q

Small molecular inhibitors and degraders targeting STAT3 for cancer therapy: An updated review (from 2022 to 2024)

Kang, Z., Shen, L., Li, Y., Song, J., Peng, Y., & Chen, Y. (2024) · Chinese Chemical Letters · doi:10.1016/j.cclet.2024.110447 · Cited by 42

Targeting the STAT3 pathway with STAT3 degraders

Wang, Z., Liao, X., He, H., Guo, X., & Chen, J. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.07.003 · Cited by 46

Discovery of STAT3 Inhibitors: Recent Advances and Future Perspectives

Song, J., Wang, J., Tian, S., & Li, H. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220819093117 · Cited by 54

Small Molecule Inhibitors of STAT3 for Cancer Therapy

Zhao, M. L., Jiang, B., & Gao, F. (2011) · Current Medicinal Chemistry · doi:10.2174/092986711796957284 · Cited by 82

Strategies and Approaches of Targeting STAT3 for Cancer Treatment

Furtek, S. L., Backos, D. S., Matheson, C. J., & Reigan, P. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b00945 · Cited by 356