Structure-Based Drug Design of Novel Triaminotriazine Derivatives as Orally Bioavailable IDH2R140Q Inhibitors with High Selectivity and Reduced hERG Inhibitory Activity for the Treatment of Acute Myeloid Leukemia

Qingyun Wei; Kun Yao; Jie Yang; Qian Zhou; Pengyu Liu; Jiao Chen; Haipeng Liu; Yisheng Lai; Peng Cao

doi:10.1021/acs.jmedchem.3c00835

Structure-Based Drug Design of Novel Triaminotriazine Derivatives as Orally Bioavailable IDH2^R140Q Inhibitors with High Selectivity and Reduced hERG Inhibitory Activity for the Treatment of Acute Myeloid Leukemia

J Med Chem. 2023 Sep 28;66(18):12894-12910. doi: 10.1021/acs.jmedchem.3c00835. Epub 2023 Sep 14.

Authors

Qingyun Wei^{1

2}, Kun Yao³, Jie Yang^{1

2}, Qian Zhou^{1

2}, Pengyu Liu³, Jiao Chen^{1

2}, Haipeng Liu³, Yisheng Lai³, Peng Cao^{1

4}

Affiliations

¹ Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.
² Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China.
³ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
⁴ School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.

PMID: 37706660
DOI: 10.1021/acs.jmedchem.3c00835

Abstract

Neomorphic IDH2^R140Q mutation is commonly found in acute myeloid leukemia (AML), and inhibiting its activity has been validated as an effective treatment for AML. Herein, we report a series of highly potent and selective IDH2^R140Q inhibitors. Among them, compound 36 was identified as the most promising inhibitor, with an IC₅₀ value of 29 nM and more than 490-fold selectivity over wild-type IDH2. The compound significantly suppressed D2HG production (IC₅₀ = 10 nM) and induced differentiation in TF-1/IDH2^R140Q cells. Furthermore, it showed reasonable pharmacokinetic properties with high bioavailability (F = 90.3%) and an appropriate half-life (T_1/2 = 6.4 h). In vivo, oral administration of compound 36 at a dose of 25 mg/kg effectively reduced D2HG levels in the tumor of TF-1/IDH2^R140Q xenograft mouse model. Besides, compound 36 displayed little effect on the hERG current. These results suggest that compound 36 has the potential to be an efficacious treatment for AML.