Pyr3 is a potent and selective inhibitor of transient receptor potential canonical channel 3 (TRPC3), with an IC50 of 700nM for TRPC3-mediated Ca2+ influx [1]. Pyr3 can reduce the secretion level of MMP9 in cells and inhibit the phosphorylation of signal transducer and activator of transcription (STAT) 5[2]. Pyr3 has been widely used to inhibit the proliferation and migration of melanoma, as well as to regulate tumor growth and metastasis[3].
In vitro, Pyr3 treatment for 48 hours significantly inhibited the proliferation of A549 cells, HCT-116 cells, and PC3 cells, with IC50 values of 15.4, 7.9, and 2.3μg/ml, respectively[4]. Treatment with 10μM Pyr3 for 24 hours significantly inhibited the viability of T24 cells, induced cell cycle arrest, and decreased the expression levels of p-PKCα, PKCα and PP2A[5]. Treatment with 1.0μM Pyr3 for 8 hours significantly induced apoptosis in MDA-MB-231 cells, accompanied by cell contraction, cell membrane blebbing, mitochondrial fragmentation and nuclear condensation[6].
In vivo, Pyr3 treatment via intraperitoneal injection at a dose of 20mg/kg/day for seven consecutive days significantly inhibited the growth of glioma tumors in the xenograft mouse model[7]. Five minutes before reperfusion, 10mg/kg of Pyr3 was administered via the right jugular vein to the mice, which significantly reduced the infarcted area of the left ventricle in the mice, and decreased the rate of myocardial cell apoptosis and inflammatory response[8].
References:
[1] Kiyonaka S, Kato K, Nishida M, et al. Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound[J]. Proceedings of the National Academy of Sciences, 2009, 106(13): 5400-5405.
[2] Oda K, Umemura M, Katsumata M, et al. Transient receptor potential cation channel 3 (TRPC3) regulates tumor proliferation and migration of BRAF wild type human malignant melanoma[J]. Cancer Research, 2015, 75(15_Supplement): 4371-4371.
[3] Umemura M, Baljinnyam E, De Lorenzo M S, et al. Role of store-operated Ca2+ entry in proliferation and cell cycle in melanoma[J]. Cancer Research, 2012, 72(8_Supplement): 1864-1864.
[4] Kıyan H T, Üvez A, Erkisa M, et al. A Comparative Study on In vitro Anti-cancer and In vivo Anti-angiogenic Effects of TRPC Blockers Pyr-3 and SKF-96365[J]. Letters in Drug Design & Discovery, 2023, 20(7): 957-964.
[5] Ting H K, Dou Y C, Lin Y H, et al. Pyr3 inhibits cell viability and PKCα activity to suppress migration in human bladder cancer cells[J]. European Journal of Pharmacology, 2025, 988: 177235.
[6] Wang Y, Qi Y X, Qi Z, et al. TRPC3 regulates the proliferation and apoptosis resistance of triple negative breast cancer cells through the TRPC3/RASA4/MAPK pathway[J]. Cancers, 2019, 11(4): 558.
[7] Chang H H, Cheng Y C, Tsai W C, et al. Pyr3 induces apoptosis and inhibits migration in human glioblastoma cells[J]. Cellular Physiology and Biochemistry, 2018, 48(4): 1694-1702.
[8] Lu M, Fang X, Shi D, et al. A selective TRPC3 inhibitor Pyr3 attenuates myocardial ischemia/reperfusion injury in mice[J]. Current Medical Science, 2020, 40(6): 1107-1113.
Pyr3是瞬时受体电位经典通道3（TRPC3）的一种强效、选择性抑制剂，对TRPC3介导的钙离子内流的IC50为700nM[1]。Pyr3能降低细胞中MMP9的分泌水平，并抑制信号转导和转录激活因子5的磷酸化[2]。Pyr3已广泛用于抑制黑色素瘤的增殖和迁移，以及调节肿瘤的生长和转移[3]。
在体外，Pyr3处理48小时显著抑制了A549细胞、HCT-116细胞和PC3细胞的增殖，IC50值分别为15.4μg/ml、7.9μg/ml和2.3μg/ml[4]。用10μM的Pyr3处理24小时显著抑制了T24细胞的活力，诱导了细胞周期阻滞，并降低了p-PKCα、PKCα和PP2A的表达水平[5]。用1.0μM的Pyr3处理8小时显著诱导了MDA-MB-231细胞的凋亡，伴随细胞收缩、细胞膜起泡、线粒体碎片化和核固缩[6]。
在体内，以20mg/kg/day的剂量连续七天腹腔注射Pyr3显著抑制了异种移植小鼠模型中胶质瘤的生长[7]。再灌注前五分钟通过右颈静脉给小鼠注射10mg/kg的Pyr3，显著减小了小鼠左心室的梗死面积，并降低了心肌细胞凋亡率和炎症反应 [8]。