What question did this study set out to answer?

The aim is to develop KC12 as a selective dual inhibitor of Pim and Mnk kinases to combat myeloid leukemia.

April 5, 2026

Abstract 325: Development of the pyridopyrimidine derivative KC12 as a selective dual Pim/Mnk inhibitor to inhibit leukemia cell growth.

Puntos clave

The aim is to develop KC12 as a selective dual inhibitor of Pim and Mnk kinases to combat myeloid leukemia.
Optimized the dual inhibitor 21o to create KC12 using molecular docking techniques.
Tested KC12 for its kinase inhibitory activity and selectivity against various kinases.
Assessed the pharmacokinetic profile of KC12 compared to 21o using in vivo models.
Evaluated anti-proliferative effects and mechanisms of action (cell cycle arrest and apoptosis) in K562 and MOLM-13 cells.
KC12 demonstrated improved kinase inhibition with IC50 values for Mnk1 at 32 nM, Mnk2 at 3 nM, and Pim1 at 32 nM.
Achieved better selectivity with only 4 out of 42 kinases inhibited over 40% at 100 nM.
Induced G0/G1 phase cell cycle arrest and apoptosis in leukemia cell lines.
Showed enhanced anti-tumor activity in MOLM-13 xenograft models compared to previous compound 21o.

Resumen

Abstract Myeloid leukemia is an abnormal proliferative disease relying on fast cap-dependent protein translation. Both provirus integration in Maloney murine leukemia virus (Pim) kinases and mitogen-activated protein kinase-interacting kinases (Mnk) play key roles in activating cap-dependent translation, making them attractive targets for anticancer drug development. Although several selective Pim or Mnk inhibitors entered clinical trials, their efficacy was limited. We propose that concurrent inhibition of both Pim/Mnk kinases is necessary for effective treatment. Previously, we reported the first dual Pim and Mnk inhibitor 21o with a pyrido3,2-d pyrimidine core (IC50 Mnk1: 9 nM, Mnk2: 5 nM, Pim1: 120 nM), but suffered from poor solubility. We optimized 21o based on molecular docking and obtained a compound KC12 with enhanced kinase inhibitory activity (IC50 Mnk1:32 nM, Mnk2 3 nM; Pim 1 32 nM) and improved selectivity (only 4 out of 42 tested kinases showed 40% inhibition at 100 nM). KC12 exhibits increased aqueous solubility and superior anti-proliferative activity compared to 21o, as well as to the Pim inhibitor TP-3654 and the Mnk inhibitor eFT508. KC12 induced G0/G1 phase cell cycle arrest in K562 cells and apoptosis in MOLM-13 cells, correlated to the suppression of both eIF4E and 4EBP1 phosphorylation, and the cap-dependent translation products c-Myc and Mcl-1. Moreover, KC12 demonstrated a more favorable pharmacokinetic profile than 21o and exhibited enhanced antitumor efficacy in MOLM-13 xenograft models. These findings suggest that KC12 acts as a novel, potent, and selective dual Pim/Mnk inhibitor and is worthy of further development as a therapeutic agent. Citation Format: Linxiang Zhao, Kun Xing, Jingyi Zhang, Shuwei Zuo, Fuyao Zhang, Samuel Waxman, Yongkui Jing. Development of the pyridopyrimidine derivative KC12 as a selective dual Pim/Mnk inhibitor to inhibit leukemia cell growth abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 325.

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