2. Academic Validation
  3. Discovery of 1,2,3,4-Tetrahydrochromeno[3,4- c]pyridin-5-one Derivatives as Novel MTHFD Inhibitors for the Treatment of Acute Myeloid Leukemia

Discovery of 1,2,3,4-Tetrahydrochromeno[3,4- c]pyridin-5-one Derivatives as Novel MTHFD Inhibitors for the Treatment of Acute Myeloid Leukemia

  • J Med Chem. 2026 Apr 9;69(7):8476-8502. doi: 10.1021/acs.jmedchem.6c00023.
Hao Lin 1,  Xiangli He 2,  Bin Sun 3,  Haowen Lu 2,  Jun Liang 2,  Qinghua Wang 1,  Jingjing Liao 2,  Xinyu Yang 4,  Zilan Song 1,  Junke Zheng 5,  Weiqiang Lu 4 6,  Ao Zhang 1
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240 China.
  • 2 Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 3 School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563003, China.
  • 4 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200237, China.
  • 5 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 6 Center for Drug Discovery & Translational Medicine, Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs and Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou 571199, China.
PMID: 41859783 DOI: 10.1021/acs.jmedchem.6c00023
Abstract

One-carbon metabolism is essential for nucleotide biosynthesis and redox homeostasis, and its key Enzymes, MTHFD2 and MTHFD1, are aberrantly activated in diverse cancers, particularly acute myeloid leukemia (AML). Herein, we solved the X-ray crystallography of the reported MTHFD inhibitor DS18561882 bound to MTHFD2 and performed systematic structure-activity optimization, leading to the identification of a highly selective MTHFD2 inhibitor (compound 31) and a dual MTHFD1/2 inhibitor (compound 34). Cocrystal structural analysis revealed that subtle modifications of the aminosulfonamide motif dictate isoform selectivity by reshaping hydrogen bond and hydrophobic networks within the MTHFDs active site. Notably, the dual inhibitor 34 exhibited superior antiproliferative activities across AML cell lines and induced marked tumor regression in MOLM-13 xenograft models with minimal toxicity, outperforming the reference compound DS18561882. Our findings establish rational design principles for isoform-selective and dual MTHFD1/2 inhibitors and highlight a combined MTHFD1/2 blockade as a promising therapeutic strategy for AML.

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