https://orcid.org/0000-0002-4223-7191
Abstract
Lymphoma, a blood tumor, has become the ninth most common cancer in the world in 2020. Targeted inhibition is one of the important treatments for lymphoma. At present, there are many kinds of targeted drugs for the treatment of lymphoma. Studies have shown that Histone deacetylase, Bruton's tyrosine kinase and phosphoinositide 3-kinase all play an important role in the occurrence and development of tumors and become important and promising inhibitory targets. This article mainly expounds the important role of these target protein in tumors, and introduces the mechanism of action, structure–activity relationship and clinical research of listed small molecule inhibitors of these targets, hoping to provide new ideas for the treatment of lymphoma.
Background
Lymphoma has become the ninth most common cancer in the world.
Targets & inhibitors
Histone deacetylase (HADC) is a key regulator that controls the transcription process. It can affect the proliferation, apoptosis, angiogenesis and cell growth of tumor cells, and thus becomes a promising target.
Vorinostat, Romidepsin, Belinostat and Panobinostat are HADC inhibitors which approved by the FDA for lymphoma treatment. However, their selectivity is not high and they are prone to adverse events.
Bruton's tyrosine kinase (BTK) is an important kinase in the BCR pathway, which is mainly involved in the control of B cell growth, proliferation and apoptosis. Because of the abnormal expression of BCR signaling pathway found in a variety of B cell lymphomas, BTK has become a hot target.
There are four BTK inhibitors approved by FDA for lymphoma treatment: Ibrutinib, Acalabrutinib, Zanubrutinib and Pirtobrutinib. However, the mutation of Cys481 makes Ibrutinib, Acalabrutinib and Zanubrutinib lose their efficacy. Although Pirtobrutinib does not use Cys481 as the active site, its mechanism of action and adverse events still need further study.
Hosphoinositide 3-kinase (PI3K) is the center of the PI3K-Akt-mTOR signaling pathway. It has been found to be overexpressed in a variety of cancers and has become a potential target for a variety of cancers. Among them, PI3Kδ has become one of the therapeutic targets for lymphoma because of its effect on immune cells.
Three PI3K inhibitors approved by the FDA for the treatment of lymphoma, namely Idelalisib, Copanlisib and Duvelisib. How to reduce the occurrence of adverse reactions while maintaining the efficacy is still a problem that PI3K inhibitors need to solve.
Conclusion & prospect
Multi-drug combination or combination of multiple therapies may become one of the feasible solutions to solve the adverse events or drug resistance of existing small molecule target inhibitors in the future.
The development of multi-target inhibitors may be an effective solution.
Supplemental material
Supplemental data for this article can be accessed at https://doi.org/10.1080/17568919.2024.2359893
Acknowledgments
The authors express their sincere gratitude to the Zhejiang University of Technology for supporting the access to databases needed for the literature survey.
Financial disclosure
This research was supported by the Zhejiang Provincial Natural Science Foundation of China under Grant No. LY19B020008, the Science and Technology Program of Zhejiang Province (Key Innovative Team) under Grant No. 2018R01015, the New-shoot Talents Program of Zhejiang Province under Grant No. 2024R403049, and the National Undergraduate Training Program for Innovation and Entrepreneurship of China under Grant No. 202310337001. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.