The Vanilloid group (TRPV) contains six members, from TRPV1 to TRPV6. TRPV5 and TRPV6 exhibit lower sequence identity to V1-V4, and different properties. Additionally, TRPV5 or TRPV6 is selective for calcium ions. The major function of TRPV5/6 is larger-scale calcium homeostasis. Besides, Mice with TRPV6 knock-outs exhibit defective intestinal Ca2+ absorption, reduced fertility, and increased urinary calcium. The overexpress of TRPV6 exhibits upregulation in K-562 and SW480, LNCaP, and PC-3.
In this article, we will introduce a potent and selective TRPV6 antagonist, SOR-C13.
SOR-C13 is a first-in-human TRPV6 calcium channel inhibitor. SOR-C13 binds to and inhibits calcium influx through TRPV6 with an EC50 of 14 nM. In vitro, SOR-C13 reduces the amplitude of the TRPV6 currents. 83.5 nM, 417.5 nM, 835 nM, and 25 µM SOR-C13 reduces the amplitude of the TRPV6 currents by 18±4.0%, 22±4%, 24±4%, and 25±5%, respectively. What’s more, SOR-C13 is more effective at reducing cell viability than cis-Platin. This peptide deliveres a conjugated fluorescent label to TRPV6-rich xenografts.
RPV6 is a non-voltage gated calcium channel that is associated with malignancy and poor prognosis in breast cancer. In a mice model, SOR-C13 leads to 5% weight loss. Furthermore, all mice in the SOR-C13 group have normal fur while mice receiving chemotherapeutic drugs show some ruffling of fur. But all mice are within health standards requirements.
In SKOV-3 tumors, SOR-C13 leads to a reduction of tumor growth. Additionally, 665 mg/kg of neat SOR-C13 (425 μmole/kg) provides 59% inhibition of tumor growth. Meanwhile, 494 mg/kg of neat SOR-C27 (167 μmole/kg) produces similar inhibition (55%).
In conclusion, SOR-C13 is a high-affinity TRPV6 antagonist for advanced solid tumors research.
Reference:
Hui Xue, et al. J Cancer. 2018 Aug 6;9(17):3196-3207.