Proof-of-concept and drug candidate discovery of CHK1/FLT3 dual-targeted inhibitors

Acute myeloid leukemia (AML) is a hematologic malignancy
caused by abnormal proliferation of myeloid blasts in the bone marrow, peripheral blood, or extramedullary tissue.
In recent years, the incidence of AML and drug-resistant mutations have continued to rise, among which FLT3 mutation is the most common gene mutation in AML, accounting for about 30% (Leukemia, 2019, 33: 299-312).

FLT3-ITD mutation is one of the independent adverse prognostic factors in AML patients, which is prone to recurrence, short survival time, and does not respond well
to traditional chemotherapy.
Targeted inhibition of FLT3 is an important means to resist FLT3 mutant AML, and FLT3 inhibitors such as midostaurin, gilteritinib and quizartinib have been approved for marketing in the United States or Japan, but the adaptability and acquired resistance of FLT3 inhibitors after treatment are key issues
that need to be solved in clinical practice.

Based on the above challenges, the Li Jia research group of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and the Liu Tao research group of the School of Pharmaceutical Sciences of Zhejiang University published the latest research results "Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired" in the journal Leukemia on December 16, 2022 resistance in FLT3-ITD acute myeloid leukemia”
。 This achievement first proposed and verified that dual-targeted CHK1/FLT3 can overcome FLT3 inhibitor resistance, which is a new strategy to overcome the adaptive and acquired resistance of FLT3 inhibitor therapy in AML patients, and developed a dual-targeted CHK1/FLT3 inhibitor candidate 30 (TLX83)
with good druggability.

Based on the synergistic potential of CHK1 inhibitors and FLT3 inhibitors in combination with FLT3 inhibitors, this study proposed the concept of innovative drug development with dual targeted inhibition of CHK1/FLT3, and identified TLX83, a preclinical candidate molecule for dual targeted inhibition of FLT3/CHK1, which can not only strongly inhibit the growth of a variety of FLT3-acquired mutant cells, but also fight cytokine-induced adaptive resistance.
Moreover, it can significantly improve the survival of a variety of
FLT3 mutant AML-bearing mice.
The mechanism study showed that TLX83 could significantly inhibit the FLT3 and CHK1-related pathways, downregulate the c-Myc pathway, and significantly activate the p53 pathway.
p53 knockout significantly reversed TLX83's ability to resist adaptive resistance, indicating that p53 pathway activation plays an important role
in TLX83 overcoming adaptive resistance to FLT3 inhibitors.

TLX83 has good druggability, stable metabolism in liver microsomes of various species including humans, good metabolic properties of oral drugs in mice, rats and dogs, no obvious blood toxicity such as bone marrow suppression, and has a good safety window
.
A comprehensive systematic preclinical study of TLX83 is currently underway and is expected to be filed for clinical
trials in 2023.

Researcher Zhou Yubo, researcher Li Jia and associate professor Liu Tao of Zhejiang University are co-corresponding authors of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Institute of Drug Innovation, Chinese Academy of Sciences, assistant researcher Dr.
Jiang Kailong, associate senior experimentalist, Li Xuemei, doctoral student of School of Pharmacy, Zhejiang University, and Wang Chang, intermediate engineer of Shanghai Institute of Materia Medica, are co-first authors
.
The work was supported
by Guangdong High-level New R&D Institute, Guangdong High-level Innovation Research Institute, National Natural Science Foundation of China, Zhejiang Natural Science Foundation of Zhejiang Province, Shanghai Science and Technology Commission, etc.

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