Herman Sintim

Research Interests

Cyclic Dinucleotide Signaling

The ability of cells to sense and respond to environmental cues is critical for survival. Cells integrate environmental cues to regulate the synthesis and degradation of second messengers, which mediate many essential processes in archaea, eubacteria, and eukaryotes. Cyclic dinucleotides, such as c-di-GMP, c-di-AMP, and cGAMP, are second messengers in all three domains of life. In Gram-negative bacteria, Gram-positive bacteria, and mycobacteria, cyclic dinucleotides orchestrate a dizzying array of processes that include biofilm formation, virulence factors production, cell wall remodeling, and antibiotic resistance. Cyclic dinucleotides also affect mammalian cells, particularly immune cells, and play important roles related to inflammation, T-cell maturation, and antigen presentation. Due to the essential roles played by these fascinating second molecules, there are now intense research efforts to identify macromolecular targets in the cell that sense these molecules. Recently, the activation of immune response to cyclic dinucleotides (CDNs) via STING has come to the forefront. Many drug companies have initiated programs aimed at identifying activators or inhibitors of STING as cancer immunotherapy and anti-inflammatory agents respectively.

The Sintim group has a long-standing interest in the development of cyclic dinucleotide probes to illuminate CDN biology, identifying small molecule inhibitors of CDN signaling in bacteria with potential use as novel antibacterial agents. The group is also interested in identifying and optimizing potential therapeutics that agonize STING (immunotherapies) or antagonize STING (anti-inflammatory compounds).

Synthesis of Novel Kinase Inhibitors via Multi-component Reactions

Kinase inhibitor (KI) therapy has revolutionized cancer treatment. Therapeutic resistance to KIs, however, remains a critical issue in cancer treatment. While cancer patients who harbor dysregulated protein kinases benefit from the use of kinase inhibitors (KIs), many fail therapy, and almost all patients become resistant to treatment, indicating a critical unmet need to prevent treatment failure. Although many compounds that inhibit protein kinases have been described in the literature, only a small region of the chemical space has been explored for protein kinase inhibition, and the majority of FDA approved kinase inhibitors contain only a handful of core moieties, such as indazole, quinoline, isoquinoline, quinazoline, pyrazole and pyrimidine.

The Sintim group is interested in developing kinase inhibitors that inhibit secondary mutated kinases, which play important roles in drug resistance (i.e. cancer intrinsic pathways) and/or inhibitors that target kinases that regulate the tumor microenvironment (i.e. cancer extrinsic pathways). Integrating computational and experimental workflows, such as the use of multi-component reactions to prepare novel kinase inhibitor libraries, the Sintim lab has identified novel chemotypes that inhibit disease-associated protein kinases (such as Tak1, FLT3, RET, CDKs, Haspin, HUNK) with sub-nanomolar IC 50 values. Some of these new KIs are long residence time (hours) inhibitors and have shown impressive efficacies in animal models of various cancers.

Selected Publications

• Asmi, A. R.; Akwata, D.; Hunjan, M. K.; Dayal, N. and Sintim, H. O. "2-Morpholino-Substituted Imidazothiadiazole TAK1 Inhibitors for Reduction of Proinflammatory Cytokines" 2026 European Journal of Medicinal Chemistry Reports, 17, 100344. DOI: 10.1016/j.ejmcr.2026.100344.
• Hanuman, D. S.; Neeharika, S.; Murari, S. K.; Yeboah, S. K.; Sintim, H. O. and Rajakumara, E. "Structural and Biochemical Insights into the Inhibition of Mycobacterium tuberculosis Cyclic Dinucleotide Phosphodiesterase by a Sulfur-Modified Cyclic Dinucleotide Analog" 2026 RSC Chemical Biology, 7 (5), pp.880–891. DOI: 10.1039/d6cb00006a.
• Dayal, N.; Eva, R.; Hernandez, D. E.; Perina, M.; Belícek, J.; Vojácková, V.; Krnávková, P.; Barina, M.; Brauer, N. R.; Hunjan, M. K.; Yadav, P.; Jorda, R. and Sintim, H. O. "3H-pyrazolo[4,3-F]quinoline Hinge Binder, a Tunable Scaffold for Development of Novel Kinase Inhibitors Against FLT3-Driven Leukemia" 2026 European Journal of Medicinal Chemistry, 302, 118309. DOI: 10.1016/j.ejmech.2025.118309.
• Naclerio, G. A.; Vennard, C. S.; Onyedibe, K. I.; Vieira, D. D.; Abutaleb, N. S.; Figueiredo, M. L.; Seleem, M. N. and Sintim, H. O. "Halogenated N-(1,3,4-oxadiazol-2-yl) Benzamides are Effective Eradicators of Methicillin-Resistant Staphylococcus aureus Biofilms" 2026 Bioorganic & Medicinal Chemistry, 132, 118437. DOI: 10.1016/j.bmc.2025.118437.
• Priya, R.; Ye, M. P.; Raghunanadanan, S.; Liu, Q.; Li, W.; Yu, Q. G.; Lou, Y. L.; Sintim, H. O. and Yang, X. F. "Borrelia burgdorferi c-di-AMP is a Key Extracellular Pathogen-Associated Molecular Pattern to Elicit Type I Interferon Responses in Mammalian Hosts" 2025 Journal of Immunology, 214 (9), pp.2325–2337. DOI: 10.1093/jimmun/vkaf133.
• Yeboah, S. K.; Meher, S.; Harper, H. A.; McMahan, C.; Elzey, B. D. and Sintim, H. O. "5′-Phosphorothioester Linked Cyclic Dinucleotides, Endo-S-CDNs, Displaying Impressive Antitumor Activities in Vivo when Dosed Subcutaneously" 2025 ACS Bio & Med Chem Au, 5 (4), pp.665–693. DOI: 10.1021/acsbiomedchemau.5c00070.