Reference Detail

Ref Type

Journal Article

PMID

(31361380)

Authors

Gao M, Zhu H, Fu L, Li Y, Bao X, Fu H, Quan H, Wang L, Lou L

Title

Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer science	110	10	2019 Oct	3306-3314	Cancer Sci

URL

Abstract Text

Isocitrate dehydrogenase 2 (IDH2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. AG-221, an inhibitor primarily targeting the IDH2-R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, AG-221 has weak inhibitory activity toward IDH2-R172K, a mutant form of IDH2 with more severe clinical manifestations. Herein, we report TQ05310 as the first mutant IDH2 inhibitor that potently targets both IDH2-R140Q and IDH2-R172K mutants. TQ05310 inhibited mutant IDH2 enzymatic activity, suppressed (R)-2-hydroxyglutarate (2-HG) production and induced differentiation in cells expressing IDH2-R140Q and IDH2-R172K, but not in cells expressing wild-type IDH1/2 or mutant IDH1. TQ05310 bound to both IDH2-R140Q and IDH2-R172K, with Q316 being the critical residue mediating the binding of TQ05310 with IDH2-R140Q, but not with IDH2-R172K. TQ05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2-HG production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of TQ05310, and provide new insight into the development of novel mutant IDH2 inhibitors.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
TQ05310	TQ05310	4	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TQ05310			IDH2 Inhibitor 5	TQ05310 inhibits IDH2, potentially resulting in increased differentiation and decreased proliferation of tumor cells (PMID: 31361380).

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 R172K	high grade glioma	sensitive	TQ05310	Preclinical - Cell culture	Actionable	In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in a glioma cell line expressing IDH2 R172K in culture (PMID: 31361380).	31361380
IDH2 R140Q	acute myeloid leukemia	sensitive	TQ05310	Preclinical - Cell culture	Actionable	In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in an acute myeloid leukemia cell line expressing IDH2 R140Q in culture (PMID: 31361380).	31361380
IDH2 R140Q	high grade glioma	sensitive	TQ05310	Preclinical - Cell culture	Actionable	In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in a glioma cell line expressing IDH2 R140Q in culture (PMID: 31361380).	31361380
IDH2 R172K	acute myeloid leukemia	sensitive	TQ05310	Preclinical - Cell culture	Actionable	In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in an acute myeloid leukemia cell line expressing IDH2 R172K in culture (PMID: 31361380).	31361380