PDHK Inhibitor

Dicoumarol is an inhibitor of both NAD(P)H:quinone oxidoreductase 1 (NQO1) and PDK1 with IC₅₀s of 0.37 and 19.42 μM, respectively.

AZD7545 is a potent, competitive, selective PDHK2 (pyruvate dehydrogenase kinase 2) inhibitor with IC₅₀s of 36.8 nM, 6.4 nM for PDHK1 and PDHK2, respectively.

PDK4-IN-1 hydrochloride is an anthraquinone derivative and a potent and orally active pyruvate dehydrogenase kinase 4 (PDK4) inhibitor with an IC₅₀ value of 84 nM. PDK4-IN-1 hydrochloride potently represses cellular transformation and cellular proliferation and induces apoptosis. PDK4-IN-1 hydrochloride has antidiabetic, anticancer and anti-allergic activity.

VER-246608 is a potent and ATP-competitive inhibitor of pyruvate dehydrogenase kinase (PDK) with IC₅₀s of 35 nM, 40 nM, 84 nM, and 91 nM for PDK-1, PDK-3, PDK-2, and PDK-4, respectively.

PS10 is a novel, potent and ATP-competitive pan-PDK inhibitor, inhibits all PDK isoforms with IC₅₀ of 0.8 μM, 0.76 μM, 2.1 μM and 21.3 μM for PDK2, PDK4, PDK1, and PDK3, respectively. PS10 shows high affinity for PDK2 (K_d= 239 nM) than for Hsp90 (K_d= 47 μM). PS10 improves glucose tolerance, stimulates myocardial carbohydrate oxidation in diet-induced obesity. PS10 has the potential for the investigation of diabetic cardiomyopathy.PDK: pyruvate dehydrogenase kinase

PDK4-IN-1 is an anthraquinone derivative and a potent and orally active pyruvate dehydrogenase kinase 4 (PDK4) inhibitor with an IC₅₀ value of 84 nM. PDK4-IN-1 potently represses cellular transformation and cellular proliferation and induces apoptosis. PDK4-IN-1 has antidiabetic, anticancer and anti-allergic activity.

JX06 is a potent, selective and covalent inhibitor of PDK. JX06 inhibits PDK1, PDK2 and PDK3 with IC₅₀s of 49 nM, 101 nM, and 313 nM, respectively. JX06 inhibits PDK1 activity via covalently binding to a cysteine residue in an irreversible manner. JX06 shows significant antitumor activity.

M77976 is a specific ATP-competitive inhibitor of PDK4 (pyruvate dehydrogenase kinase isoforms 4), with an IC₅₀ of 648 μM. M77976 is potential for the research of obesity and diabetes.

PF-07208254 is a selective, orally active allosteric inhibitor of branched-chain ketoacid dehydrogenase kinase (BDK) (IC₅₀=110 nM, K_i=54 nM, K_D=84 nM). PF-07208254 inhibits BDK-mediated BCKDH phosphorylation and enhances the catabolism of branched-chain amino acids (BCAAs) and branched-chain keto acids (BCKAs) by binding to the allosteric pocket of BDK, reducing BDK binding to BCKDH-E2 and promoting BDK degradation. PF-07208254 inhibits BDK activity in human skeletal muscle cells (IC₅₀=540 nM) and has activity to improve cardiac function and metabolism. PF-07208254 can be used in the study of cardiometabolic diseases (e.g., heart failure, type 2 diabetes).

TM-1 is a potent inhibitor of pyruvate dehydrogenase kinase (PDHK1). TM-1 inhibits PDHK1 and PDHK2 with IC₅₀s of 2.97 μM and 5.2 μM, respectively. TM-1 blocks pyruvate dehydrogenase complex (PDHC) phosphorylation, and inhibits cell proliferation.

ILK-IN-2 (OSU-T315 analog) is an oral PDK2 inhibitor and also an ILK inhibitor, with an IC₅₀ of 0.6 μM. ILK-IN-2 induces cell autophagy and apoptosis, showing anti-tumor activity. ILK-IN-2 directly abolishes AKT activation by preventing AKT from translocating to lipid rafts, triggering Caspase-dependent apoptosis in chronic lymphocytic leukemia (CLL) and extending the lifespan in TCL1 mouse models.

PDK-IN-1 (compound 7o) is a pyruvate dehydrogenase kinase (PDK) inhibitor. PDK-IN-1 shows IC₅₀ values of 0.03 and 0.1 μM for PDK1 and HSP90, respectively. PDK-IN-1 targets PDH/PDK axis thus reducing efficiently the tumor mass.

KPLH1130 is a pyruvate dehydrogenase kinase (PDK) inhibitor. KPLH1130 potently inhibits M1 macrophage polarization by reducing the expression of pro-inflammatory cytokines, decreasing the levels of M1 phenotype markers (HIF-1α, iNOS) and nitric oxide (NO) production. KPLH1130 prevents the reduction of mitochondrial oxygen consumption rate (OCR) induced by inflammatory stimuli (LPS ((HY-D1056) + IFN-γ) in various macrophage types. KPLH1130 improves glucose tolerance in HFD-fed mice. KPLH1130 can be used for the study of obesity-associated metabolic disorders and other inflammatory conditions.

PDK-IN-3 (compound 1) is a potent pan inhibitor of PDK with IC₅₀s of 109.3, 135.8, 458.7 nM and 8.67 μM against PDK 1-4, respectively. PDK-IN-3 also induces proliferation and apoptosis in A549 cells.

PDHK-IN-4 (Compound 30) is a potent inhibitor of PDHK with IC₅₀s of 0.0051 and 0.0122 μM for PDHK2 and PDHK4, repectively. Pyruvate dehydrogenase kinases (PDHKs) are fascinating agent targets for numerous diseases, including diabetes and cancers. PDHK-IN-4 has the potential for the research of cancer diseases.

DHNA (KIS20) is a PDH kinase 4 (PDK4) inhibitor with an IC₅₀ of 18 μM. DHNA can be used for the study of heart failure.

JTT251 is a PDHK inhibitor. JTT251 binds to the allosteric lipoamidebinding domain, resulting in only partial inhibition of PDHK enzymatic activity. JTT251 can be used for the research of cancer.

PDH E1-IN-1 (compound 24) is a selective TPP-competitive PDH E1 with an IC₅₀ value of 0.99 μM.

PDHK-IN-3 (compound 7) is a potent PDHK (pyruvate dehydrogenase kinase) inhibitor, with IC₅₀ values of 0.21 and 1.54 μM for PDHK2 and PDHK4, respectively.

PDK-IN-2 (Compound 1F) is a PDK inhibitor (IC₅₀: 68 nM). PDK-IN-2 inhibits the cellular expression of PDK1 and PDK4. PDK-IN-2 enhances mitochondrial bioenergetics, attenuates glycolytic phenotypes, and induces cell apoptosis in the mitochondrial pathway. PDK-IN-2 inhibits tumor growth in 4T1 syngeneic mice model.