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

Zhiqiang Wang; Zhibo Zhang; Yong Li; Li Sun; Dezhen Peng; Danyu Du; Xian Zhang; Luwei Han; Liwen Zhao; Ligong Lu; Hongzhi Du; Shengtao Yuan; Meixiao Zhan

doi:10.1016/j.apsb.2021.03.005

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

Acta Pharm Sin B. 2021 Jun;11(6):1526-1540. doi: 10.1016/j.apsb.2021.03.005. Epub 2021 Mar 9.

Authors

Zhiqiang Wang¹, Zhibo Zhang¹, Yong Li², Li Sun¹, Dezhen Peng¹, Danyu Du¹, Xian Zhang³, Luwei Han³, Liwen Zhao³, Ligong Lu², Hongzhi Du⁴, Shengtao Yuan¹, Meixiao Zhan²

Affiliations

¹ Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210003, China.
² Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China.
³ Sanhome Pharmaceutical Co., Ltd., Nanjing 210000, China.
⁴ School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China.

Abstract

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.

Keywords: 2-HG, 2-hydroxyglutaric acid; 2-Hydroxyglutarate; ADME, absorption, distribution, metabolism and excretion; AG-221, enasidenib; AML, acute myeloid leukemia; AUC, area under the cure; Acute myeloid leukaemia; BCRP, breast cancer resistance protein; CDX, cell-line-derived xenograft; CYP, cytochrome P450; Differentiation; EPO, erythropoietin; IC50, half maximal inhibitory concentration; LC–MS/MS, liquid chromatography–tandem mass spectrometry; MDR1, multidrug resistance protein 1; Mutant isocitrate dehydrogenase 2 (mIDH2); OAT, organic anion transporter; OATP, organic anion transporting polypeptide; OCT, organ cation transporter; PD, pharamacodynamics; PDX, patient-derived tumor xenograft; PK, pharmacokinetics; Papp, apparent permeability coefficient; Preclinical efficacy; SH1573; Tumor metabolism; mIDH2 inhibitor; mIDH2, mutant isocitrate dehydrogenase; α-KG, α-ketoglutaric acid.