KL-11743 is a potent glucose-competitive class I glucose transporter inhibitor. KL-11743 blocks glucose metabolism by inhibiting GLUT1 (IC50=115nM), GLUT2 (IC50=137nM), GLUT3 (IC50=90nM), and GLUT4 (IC50=68nM)[1-2]. KL-11743 can be used in research related to SLC7A11-high tumors and KEAP1-mutant lung cancer, as well as in combination therapy with lysosomal inhibitors for refractory lung cancer[3-4].
In vitro, leukemia cell lines, patient-derived iPSC models, and primary AML patient samples were treated with KL-11743 (500nM) for 24 hours. KL-11743 effectively inhibited glucose uptake and glycolysis while significantly increasing mitochondrial respiration, particularly by enhancing Complex I function[5]. HT22 cells were treated with KL-11743 (500nM) for 2 hours. KL-11743 significantly inhibited cell viability and suppressed the high glucose-induced increase in the glucose transporter GLUT3 expression, but did not significantly inhibit the upregulation of PIEZO1[6].
In vivo, fasted C57BL/6 mice received a single oral dose of KL-11743 (30 or 100mg/kg). KL-11743 significantly increased blood glucose levels and delayed glucose clearance; Nude mice bearing patient-derived xenograft models (with SDHA-D38V mutation) were treated orally with KL-11743 (100mg/kg) daily. KL-11743 inhibited tumor growth[7]. Mice bearing SLC7A11-high tumors (such as NCI-H226 xenografts or patient-derived xenografts) were administered KL-11743 (100mg/kg) via intraperitoneal injection every other day for 5 weeks. KL-11743 significantly suppressed the growth of SLC7A11-high tumors, selectively increased the NADP+/NADPH ratio specifically in these tumors, and caused no significant pathological changes or body weight loss[8].
References:
[1] Liu KG, Kim JI, Olszewski K, et al. Discovery and Optimization of Glucose Uptake Inhibitors. J Med Chem. 2020 May 28;63(10):5201-5211.
[2] Koppula P, Olszewski K, Zhang Y, et al. KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition. iScience. 2021 May 25;24(6):102649.
[3] Chen W, Lin C, Gao Z, et al. A tumor microenvironment-responsive nanocomposite for enhanced copper retention and hypoxia reversal to promote cuproptosis in tumor treatment. Acta Biomater. 2025 Aug;202:463-475.
[4] Wang X, Li J, Luo Z, et al. ATP-Exhausted Strategy Induced Anti-Tumor Low-Temperature Photothermal Therapy Based on Rare Earth Nanocrystals Modified Hollow Porous MnO Nanozyme with TME-Activated NIR-II Imaging. Small. 2025 Apr;21(14):e2410070.
[5] Komza M, Khatun J, Gelles JD, et al. Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival. Cell Commun Signal. 2025 Jan 25;23(1):47.
[6] Liu H, Zhou L, Wang X, et al. PIEZO1 as a new target for hyperglycemic stress-induced neuropathic injury: The potential therapeutic role of bezafibrate. Biomed Pharmacother. 2024 Jul;176:116837.
[7] Olszewski K, Barsotti A, Feng XJ, et al. Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors. Cell Chem Biol. 2022 Mar 17;29(3):423-435.e10.
[8] Liu X, Olszewski K, Zhang Y, et al. Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer. Nat Cell Biol. 2020 Apr;22(4):476-486.
KL-11743是一种高效的葡萄糖竞争性I类葡萄糖转运蛋白抑制剂，KL-11743通过抑制GLUT1（IC50=115nM）、GLUT2（IC50=137nM）、GLUT3（IC50=90nM）和GLUT4（IC50=68nM）来阻断葡萄糖代谢[1-2]。KL-11743可用于SLC7A11高表达肿瘤和KEAP1突变型肺癌的相关研究，以及与溶酶体抑制剂联合治疗难治性肺癌[3-4]。
在体外，KL-11743（500nM）处理白血病细胞系、患者来源的iPSC模型及原代AML患者样本24小时。KL-11743可有效抑制葡萄糖摄取和糖酵解，同时显著增加了线粒体呼吸，特别是增强了complex I的功能[5]。KL-11743（500nM）处理HT22细胞2小时。KL-11743显著抑制细胞活力，抑制高糖诱导的葡萄糖转运蛋白GLUT3表达增加，但不会显著抑制PIEZO1的上调[6]。
在体内，KL-11743（30或100mg/kg）单次口服用于处理禁食的C57BL/6小鼠。KL-11743显著升高了血糖水平并延迟了葡萄糖清除；KL-11743（100mg/kg）每天口服用于处理携带患者来源异种移植模型（SDHA-D38V突变）的裸鼠。KL-11743抑制了肿瘤的生长[7]。KL-11743（100mg/kg）每两日一次腹腔注射，用于处理携带SLC7A11高表达肿瘤（如NCI-H226异种移植瘤或患者来源异种移植瘤）的小鼠5周。KL-11743显著抑制了SLC7A11高表达肿瘤的生长，并选择性增加了此类肿瘤中的NADP+/NADPH比值，且未引起明显的病理变化或体重减轻[8]。