Pan-PDK degrader-1

Pan-PDK degrader-1 (Compound A1) (0-1000 nM; 24 h) potently and selectively degrades PDK1-GFP in MCF-7 PDK1-GFP cells, with a DC₅₀ of 94.6 nM, without altering mitochondrial protein homeostasis^[1].
Pan-PDK degrader-1 (1-100 nM; 24 h) potently degrades endogenous PDK1 in MCF-7, HeLa, A549 and PANC-1 cancer cells, with DC₅₀ values ranging from 8.3 to 97.0 nM, but exhibits only very low activity in cancer cell lines with low HsClpP expression and normal cell lines^[1].
Pan-PDK degrader-1 (1-1000 nM; 24 h) is a potent pan-PDK degrader in MCF-7 cells. It degrades PDK2, PDK3 and PDK4 via a post-translational mechanism, with DC₅₀ values of 9.2 nM, 9.9 nM and 11.5 nM, respectively, and does not alter the mRNA level of PDK1^[1].
Pan-PDK degrader-1 (50-200 nM; 24 h)-induced PDK1 degradation in MCF-7 cells strictly depends on HsClpP, as knockdown or inhibition of HsClpP activity abolishes this effect, while competitive binding to PDK1 or HsClpP interferes with the degradation process^[1].
Pan-PDK degrader-1 (100 nM-10 μM; 24 h) induces PDK1 degradation in MCF-7 cells independent of the ubiquitin-proteasome system and autophagy-lysosome pathway, relying solely on HsClpP-mediated proteolysis^[1].

Pan-PDK degrader-1 (1-5 μM; 4-12 h) reprograms the metabolism of MCF-7 cells by inhibiting glycolysis and enhancing oxidative phosphorylation at relatively low concentrations, thereby reducing lactate production^[1].

Pan-PDK degrader-1 (1-5 μM; 4 h) induces concentration-dependent accumulation of total ROS, intracellular superoxide, and mitochondrial superoxide in MCF-7 cells, and this effect is inhibited by antioxidant treatment^[1].

Pan-PDK degrader-1 (1-5 μM; 4-6 h) selectively induces loss of mitochondrial membrane potential (MMP), opening of mitochondrial permeability transition pore (mPTP) and cytochrome c release in MCF-7 cancer cells, but exerts no such effects in normal Beas-2B or HS-5 cells, thereby triggering mitochondrial dysfunction^[1].

Pan-PDK degrader-1 (50 nM-5 μM; 24-72 h) potently inhibits the proliferation of MCF-7 and MCF-7 PDK1-GFP cells and induces endogenous mitochondrial apoptosis in these cells. Its activity depends on the expression of HsClpP, while it exhibits extremely low toxicity toward normal cells^[1].

Pan-PDK degrader-1 (1-10 μM; 6 h) induces typical immunogenic cell death (ICD) events in MCF-7 PDK1-GFP cells, including concentration-dependent cell surface exposure of CRT, HMGB1 release, and increased extracellular ATP levels^[1].