2. Academic Validation
  3. Discovery of 2-(methylamino)-5,6,7,8-tetrahydropyrido[4,3-d] pyrimidine derivatives as novel HsClpP activators for multiple myeloma therapy

Discovery of 2-(methylamino)-5,6,7,8-tetrahydropyrido[4,3-d] pyrimidine derivatives as novel HsClpP activators for multiple myeloma therapy

  • Eur J Med Chem. 2026 Feb 26:309:118723. doi: 10.1016/j.ejmech.2026.118723.
Xiang Liu 1,  Jinglong Gu 2,  Yan Liu 2,  Hong Liu 2,  Bo Ren 2,  Linjie Li 2,  Tao Yang 3,  Ting Niu 4,  Yuhuan Zheng 5,  Youfu Luo 6
Affiliations

Affiliations

  • 1 Department of Hematology, Institute of Hematology, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 2 Department of Hematology, Institute of Hematology, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 Department of Hematology, Institute of Hematology, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 4 Department of Hematology, Institute of Hematology, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, China. Electronic address: [email protected].
  • 5 Department of Hematology, Institute of Hematology, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 6 Department of Hematology, Institute of Hematology, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Tianfu Jincheng Laboratory, Chengdu, 610093, China. Electronic address: [email protected].
PMID: 41785829 DOI: 10.1016/j.ejmech.2026.118723
Abstract

Chemical activation of Homo sapiens caseinolytic protease P (HsClpP) has been recognized as a promising Anticancer strategy for diverse malignancies, yet its applicability to multiple myeloma (MM) remains largely uncharted. Here, we found that D215, a HsClpP activator, exerted anti-MM activity in vitro. Using D215 as the lead compound, we obtained a series of 2-(methylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine derivatives via N-methylated modification and structural optimization, among which GU18 was ultimately selected for its remarkable activity and safety. Compared with D215, GU18 had increased HsClpP agonistic activity (EC50 = 0.54 ± 0.12 μM), enhanced anti-MM efficacy in vitro (IC50 = 0.08 ± 0.01 μM) and improved selectivity (selectivity index = 26.13-342.37) across normal cells. Mechanistic studies demonstrated that GU18 induced both structural and functional impairment of mitochondria, leading to the activation of Apoptosis in MM cells. Furthermore, GU18 exhibited robust anti-MM activity in vivo, effectively suppressing tumor growth while showing a favorable safety profile. Pharmacokinetic analysis further confirmed its optimal stability and bio-availability in vivo. Collectively, our findings identify GU18 as a promising novel candidate for MM treatment by targeting HsClpP.

Keywords

GU18; HsClpP; Methylation; Multiple myeloma.

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