Acute myeloid leukemia (AML) is a fatal form of hematopoietic malignancies. current treatment for AML involves multiple cycles of high-dose cytarabine (Ara-C) treatment, this kind of treatment impairs the quality of life of the patients. Besides, most elderly patients cannot bear robust chemotherapy. Therefore, it is important to develop a new therapeutic strategy to avoid intensive chemotherapy.
The Ten-eleven translocation (TET) proteins can convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and lead to DNA demethylation. TET-1 plays a vital role in the development of myeloid malignancies. Also, TET1 level upregulates in MLL-rearranged AML. Moreover, there exists a fact that knockout of Tet1 expression erects an extremely small effect on normal development including hematopoiesis.
From all the above, TET1 is a charming therapeutic target for AML.

In this article, we will introduce an NSC370284 analog, UC-514321. UC-514321 represses TET1 expression, but not TET2 or TET3. And UC-514321 possesses a higher activity when it compares to NSC370284.

Firstly, UC-514321 exhibits an improved effect in repressing the viability of TET1-high AML in a dose-dependent manner, including MONOMAC-6, THP-1, and KASUMI-1 cells. However, UC-514321 has no inhibitory effect on the viability of TET1-low AML, such as NB4 cells. Compared with JAK and/or STAT inhibitors, UC-514321 is effective and selective when it suppresses the viability of TET1-high AML cells.

In the AE9a-AML model. UC-514321 treatment by intraperitoneal injection prolongs the median survival of mice to 160 days. This result is much longer than NSC-370284 ( 114 days) and control (46 days) treatment.
Lastly, in two other AML models: MLL-AF10 AML and FLT3-ITD/NPM1mut AML46 model, UC-514321 shows a prominent therapeutic effect, it prolongs the median survival of MLL-AF10 and FLT3-ITD/NPM1mut leukemic mice to >50 days. However, it’s analog NSC-370284 prolongs survival of MLL-AF10 leukemic mice and that of FLT3-ITD/NPM1mut leukemic mice from 21 days to 34 days.
All in all, TET1 is a druggable target to suppress TET1 signaling. UC-514321 exhibits a decent selectivity and also a high efficacy in targeting TET1-high AML. The compound has the potential for AML treatment.


Jiang X, et al.  Nat Commun. 2017 Dec 13;8(1):2099.