Scientists announced new discoveries about the oncogene, ASH1L, which may one day lead to new treatments for leukaemia and other cancers.
Overexpression of ASH1L is known to be linked to breast cancer and leukaemia. Dr Łukasz Jaremko and colleagues at King Abdullah University of Science and Technology, Saudi Arabia, have been working on small molecule drugs that selectively attach to ASH1L and inhibit its action.
However, recent findings by other research teams had claimed that another protein called MRG15 may be an activator of ASHL1, and could block the action of the ASHL1 inhibitors. MRG15 plays many other important roles in the cell, so it is unsuitable as a drug target itself.
Researcher Dr Samah Al-Harthi commented: “Taken together, these studies gave us more insights into ASH1L enzymatic regulation by an additional co-regulator; however, it also allowed us to carefully consider other players when designing targeted drugs.”
So, the team went on to further investigate the interaction between these two proteins, ASHL1 and MRG15. They concluded that MRG15 is in fact neither an activator of ASH1L, nor does it stop their drugs binding to it, “affirming the validity of our earlier work,” said Dr Al-Harthi.
Dr Jaremko added: “Normally in biology, what you find is that systems are more complex than originally thought. In this case, the system is very simple and there was no need to make it more complex.”
The new work appeared recently in the journal Structure. Now, the team are refocusing on inhibitors of ASH1L, with the aim of developing targeted drugs in the future.
Al-Harthi S, Li H, Winkler A, Szczepski K, Deng J, Grembecka J, Cierpicki T, Jaremko Ł. (2023) “MRG15 activates histone methyltransferase activity of ASH1L by recruiting it to the nucleosomes.” Structure, doi: 10.1016/j.str.2023.07.001
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