ClpP activator-2

ClpPactivator-2 (Compound GU18) serves as a ClpP activator with a binding affinity (Kd) of 5.01 μM for HsClpP. It enhances the proteolytic activity of HsClpP and facilitates the degradation of α-casein, exhibiting an EC50 of 1.09 μM. Additionally, ClpPactivator-2 induces mitochondrial reactive oxygen species (ROS) accumulation, causing structural and functional mitochondrial damage. The compound demonstrates significant in vivo activity against multiple myeloma.

ClpP activator-2 is a potent activator of purified HsClpP with an EC₅₀ of 0.54 ± 0.12 μM. After 2 hours of treatment, ClpP activator-2 facilitates the degradation of α-casein by HsClpP with an EC₅₀ of 1.09 ± 0.08 μM. The compound binds to purified HsClpP, with an ITC-determined dissociation constant (K_d) of 5.01 ± 1.05 μM. A 24-hour treatment with 0.45 μM ClpP activator-2 results in significant mitochondrial ultrastructural damage in AMO.1 MM cells. Furthermore, a concentration-dependent accumulation of mitochondrial reactive oxygen species (ROS) occurs in AMO.1 and ARP1 multiple myeloma (MM) cells after 48 hours of treatment with ClpP activator-2 at concentrations ranging from 0.15 to 0.6 μM.

ClpP activator-2 (administered intraperitoneally at 5-30 mg/kg every other day for 14 days) can dose-dependently inhibit tumor growth in multiple myeloma within NOD/SCID mice.