Targeted small molecule therapy and inhibitors for lymphoma

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. Lymphoma has become the ninth most common cancer in the world. 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. 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.