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.