Selective TRPV2 Antagonists Derived from the Natural Product Piperlongumine Inhibit Cancer Cell Migration and...

Area of Science:

• Molecular pharmacology
• Cancer biology
• Neuroscience

Background:

• Transient Receptor Potential Vanilloid 2 (TRPV2) is implicated in cancer metastasis, pain, and inflammation.
• Existing TRPV2 modulators, like piperlongumine (PL), lack selectivity, hindering functional studies.
• There is a need for selective TRPV2 antagonists to understand its role in disease and for therapeutic development.

Purpose of the Study:

• To design and synthesize novel, selective TRPV2 antagonists based on the piperlongumine scaffold.
• To evaluate the potency, selectivity, and mechanism of action of these new derivatives.
• To assess the therapeutic potential of selective TRPV2 antagonists in cancer models.

Main Methods:

• Rational design of piperlongumine derivatives to eliminate covalent off-target activity.
• Electrophysiology and calcium fluorescence imaging to assess TRPV2 antagonist activity.
• Cellular thermal shift assays, molecular dynamics, and docking for mechanism studies.
• Chemoproteomic strategies with photoaffinity probes for proteome-wide selectivity assessment.
• In vitro cancer cell migration assays and in vivo metastasis models.

Main Results:

• Identified HKC54 as a potent TRPV2 antagonist (IC50 = 0.4 μM) with high selectivity over TRPV1 and TRPA1.
• Demonstrated direct engagement of TRPV2 by derivatives using cellular thermal shift assays.
• Chemoproteomic analysis revealed high selectivity of derivative HKC22 for TRPV2, with no detected off-targets.
• Piperlongumine derivatives inhibited cancer cell migration in vitro and suppressed metastasis in vivo.

Conclusions:

• Developed highly potent and selective TRPV2 antagonists with therapeutic potential.
• The novel derivatives offer improved tools for studying TRPV2 function in health and disease.
• Selective TRPV2 antagonism shows promise for inhibiting cancer metastasis.