ClpP Activator

Anticancer agent 230 (example 65) is a caseinolytic protease P (ClpP) activator with anticancer activity. Anticancer agent 230 is able to induce the degradation of mitochondrial proteins in SUM159 and MDA-MB-231 triple-negative breast cancer cells in a time-dependent manner.

WY165 is a bifunctional molecule comprising TR79, an activator of the mitochondrial protease complex caseinolytic protease P (ClpP), linked to desthiobiotin. WY165 mediates selective degradation of monomeric streptavidin (mSA) and its fusion proteins localized to the mitochondrial matrix with a DC₅₀ of 197 nM. WY165 restores mitochondrial morphology by reducing the level of mSA fused to short transmembrane protein 1 (mSA-STMP1) in cells overexpressing mSA-STMP1. WY165 can be used for research in cancer, neurodegenerative diseases, cardiovascular diseases, and metabolic diseases.

ClpP activator-2 (Compound GU18) is a ClpP activator with a K_d of 5.01 μM for HsClpP. ClpP activator-2 enhances the proteolytic activity of HsClpP and promotes the degradation of α-casein by HsClpP, with an EC₅₀ of 1.09 μM. ClpP activator-2 induces the accumulation of mitochondrial reactive oxygen species (ROS), leading to damage to mitochondrial structure and function. ClpP activator-2 exhibits significant in vivo anti-multiple myeloma activity.

CLPP-2068 is the orally active activator for human caseinolytic protease P (HsClpP) with an EC₅₀ of 50.4 nM. CLPP-2068 exhibits anti-proliferative efficacy in OCI-LY10 cancer cell with an IC₅₀ of 5.2 nM. CLPP-2068 decreases mitochondrial membrane potential, increases mitochondrial ROS levels, and induces mitochondrial dysfunction. CLPP-2068 arrests the cell cycle at G1 phase, and induces apoptosis in cell OCI-LY10. CLPP-2068 exhibits antitumor activity in mouse xenograft models.

NCA029 is a potent and selective homo sapiens caseinolytic protease P (HsClpP) activator with an EC₅₀ of 0.15 μM. NCA029 acts on HsClpP to activate an ATF3-dependent integrative stress response, leading to colon cancer cell death.

THX6 is an hClpP activator with an EC₅₀ of 1.18 μM. THX6 improves off-target profile with no affinity for hD2R and only weak affinity for hD3R (K_i = 51.1 µM) in HEK293 cells. THX6 shows good cytotoxicity in ONC201-resistant cells with an IC₅₀ of 0.13 μM. THX6 changes the levels of fatty acids (PUFAs, MUFAs, and SFAs) in DIPG cells. THX6 decreases the level of proteins involved in oxidative phosphorylation, biogenesis, and mitophagy proteins, thereby resulting in a global collapse of mitochondrial integrity and function. THX6 can be used for diffuse intrinsic pontine glioma research.

HsClpP activator-2 is an orally active HsClpP agonist with a K_D of 40 nM. HsClpP activator-2 potently inhibits SCLC cells including H69 (IC₅₀ = 0.17 μM) and H82 (IC₅₀ = 0.19 μM). HsClpP activator-2 disrupts mitochondrial membrane potential (MMP), as well as induces apoptosis and ROS in H82 cells. HsClpP activator-2 significantly inhibits tumor growth in non-SMC xenograft models with a tumor growth inhibition. HsClpP activator-2 can be used for the study of small cell lung carcinoma (SCLC).

ZYZ-17 is an activator of human caseinolytic peptidase P ( hClpP), with an EC₅₀ value of 0.24 μM. ZYZ-17 can be used in anticancer research.

ADEP-14 (ADEP26) is a ClpP activator. ADEP-14 exhibits antibacterial activity against Gram-negative and Gram-positive bacteria. ADEP-14 can be used in studies related to bacterial infections.

HsClpP activator-1 (compound 24) is a potent HsClpP activator with an EC₅₀ of 0.22 μM. HsClpP activator-1 effectively inhibits cancer cell growth with IC₅₀ values of 0.1-1 μM.

ACP1b is an activator for ClpP protease with K_d of 3.2 μM, and exhibits antibacterial activity. ACP1b inhibits N. meningitidis and H. influenzae with MBC of 16 and 8 μg/mL.

ACP1-01 is a bacterial ClpP activator with EC₅₀s of 3.4 and 2.6  μM for Neisseria meningitides ClpP (NmClpP) and Escherichia coli ClpP (EcClpP). ACP1-01 noncovalently binds to ClpP C sites and activates the protease. ACP1-01 has antibacterial activity. ACP1-01 can be used for bacterial infections research.