Reference Detail

Ref Type

Journal Article

PMID

(34221866)

Authors

Wang Z, Zhang Z, Li Y, Sun L, Peng D, Du D, Zhang X, Han L, Zhao L, Lu L, Du H, Yuan S, Zhan M

Title

Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Acta pharmaceutica Sinica. B	11	6	2021 Jun	1526-1540	Acta Pharm Sin B

URL

Abstract Text

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
SH1573	SH1573	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SH1573		SH 1573\|SH-1573	IDH2 Inhibitor 5	SH1573 inhibits mutant forms of IDH2, potentially resulting in increased tumor cell differentiation (PMID: 34221866).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
IDH2 R140Q	hematologic cancer	predicted - sensitive	SH1573	Preclinical - Cell culture	Actionable	In a preclinical study, SH1573 treatment decreased 2-HG levels and increased differentiation of a tumor cell line expressing IDH2 R140Q in culture (PMID: 34221866).	34221866
IDH2 R172K	hematologic cancer	predicted - sensitive	SH1573	Preclinical - Biochemical	Actionable	In a preclinical study, SH1573 inhibited the activity of IDH2 R172K in an in vitro assay (PMID: 34221866).	34221866