PDK-1 Inhibitor

Sodium dichloroacetate is an orally active pyruvate dehydrogenase kinase (PDK) inhibitor. Sodium dichloroacetate also stimulates pyruvate dehydrogenase (PDH) activity and works as a Na⁺-K⁺-2Cl⁻ cotransporter (NKCC) inhibitor. Sodium dichloroacetate prevents the phosphorylation of the E1α subunit of PDC, promoting the entry of pyruvate into the mitochondria for oxidative metabolism, reducing lactate production, and simultaneously increasing the production of reactive oxygen species (ROS). Sodium dichloroacetate inhibits tumor cell proliferation and induces apoptosis. Sodium dichloroacetate is promising for research of cancers.

BX795 is a potent and selective inhibitor of PDK1, with an IC₅₀ of 6 nM. BX795 is also a potent and relatively specific inhibitor of TBK1 and IKKε, with an IC₅₀ of 6 and 41 nM, respectively. BX795 blocks phosphorylation of S6K1, Akt, PKCδ, and GSK3β, and has lower selectivity over PKA, PKC, c-Kit, GSK3β etc. BX795 modulates autophagy.

GSK2334470 is a highly specific and potent inhibitor of PDK1 with an IC₅₀ of 10 nM.

Polyphyllin I is a bioactive constituent extracted from Paris polyphylla, has strong anti-tumor activity. Polyphyllin I is an activator of the JNK signaling pathway and is an inhibitor of PDK1/Akt/mTOR signaling. Polyphyllin I induces autophagy, G2/M phase arrest and apoptosis.

BX-912 is a direct, selective, and ATP-competitive PDK1 inhibitor (IC₅₀=26 nM). BX-912 blocks PDK1/Akt signaling in tumor cells and inhibits the anchorage-dependent growth of a variety of tumor cell lines in culture or induces apoptosis.

OXPHOS-IN-3 is a mitochondria-targeted dual OXPHOS/glycolysis inhibitor. OXPHOS-IN-3 exhibits potent antiproliferative activity against pancreatic cancer cells. OXPHOS-IN-3 induces mitochondrial dysfunction, ferroptosis, and immunogenic cell death (ICD). OXPHOS-IN-3 shows potent antitumor activity in pancreatic ductal adenocarcinoma (PDAC) models.

WH23 is a dehydrogenase/reductase SDR family member 11 (DHRS11) inhibitor with IC₅₀ values of 0.037 μM. WH23 binds to DHRS11, forming a hydrogen bond with the enzyme’s His210 residue. WH23 suppresses androgen receptor mRNA and protein expression, reduces c-Myc expression, and inhibits cancer cell proliferation. WH23 inhibits PI3K/AKT signaling by reducing phosphorylation of PDK1, AKT, mTOR, and ERK. WH23 enhances Capivasertib (HY-15431)-induced cytotoxicity and apoptosis. WH23 can be used for the research of luminal androgen receptor-positive triple-negative breast cancer.

OSU-03012 (AR-12; PDK1 inhibitor AR-12) is a blood-brain permeable PDK-1 inhibitor with an IC₅₀ of 5 μM.

TPCK (L-1-Tosylamido-2-phenylethyl chloromethyl ketone; L-TPCK) is an effective serine protease inhibitor and also a blocker of the PDK1/Akt pathway. TPCK can modify the E7 protein in actively keratinocyte cells. TPCK can induce cellular apoptosis, suppress tumor growth, reduce hypoxic-ischemic brain injury in rat pups, and affect vascular permeability in inflamed rats.

Leelamine is an orally active pyruvate dehydrogenase kinase (PDK) inhibitor with an IC₅₀ value of 9.5 μM, showing a blood glucose lowering effect in the diabetic mouse. Leelamine is also a weak agonist of cannabinoid receptors CB1 and CB2. Leelamine decreases mitotic activity, prostate-specific antigen expression and induces Apoptosis to cell death in cancer cells.

MP7 (PDK1 inhibitor) is a phosphoinositide-dependent kinase-1 (PDK1) inhibitor.

BX517 is a potent and selective inhibitor of PDK1 with IC₅₀ of 6 nM.

Lasiokaurin is an anticancer agent. Lasiokaurin can be isolated from Rabdosia rubescens (Hemsl.) H. Hara. Lasiokaurin inhibits the function of the PDPK1-AKT axis, with a K_d value of 75.93 μM for PDPK1. Lasiokaurin inhibits mTOR, STAT3, MAPK and NF-κB. Lasiokaurin reduces the mRNA and protein expression levels of PLK1. Lasiokaurin decreases DNA synthesis levels, induces cell Apoptosis, and regulates Autophagy processes. Lasiokaurin inhibits tumor growth in xenograft models. Lasiokaurin can be used in research related to nasopharyngeal carcinoma, triple-negative breast cancer.

Tyroserleutide hydrochloride is a tripeptide isolated from the degradation products of porcine spleen with antitumor activity. Tyroserleutide hydrochloride can upregulate the expression of the tumor suppressor gene PTEN and inhibit the activity of AKT and PDK1. Tyroserleutide hydrochloride inhibits tumor cell proliferation and MDM2 phosphorylation by inhibiting the PI3K/AKT pathway, and also upregulates P21, P27, P53, and induces mitochondrial damage and cell apoptosis.

PDK1-IN-RS2 is a mimic of peptide docking motif (PIFtide) and is a substrate-selective PDK1 inhibitor with a K_d of 9 μM. PDK1-IN-RS2 suppresses the activation of the downstream kinases S6K1 by PDK1.

SMART1 is a highly specific and CRBN-dependent PROTAC that can effectively degrade Smurf1. SMART1 can block the PDK1-Akt signaling pathway in KRAS mutant colorectal cancer. SMART1 can inhibit tumor growth in KRAS mutant colorectal cancer (CRC) xenograft models.

BX-320 is a selective, ATP-competitive, orally acitive, and direct PDK1 inhibitor with an IC₅₀ of 30 nM in a direct kinase assay format. BX-320 also induces apoptosis. Anticancer effect.

PKD-IN-1 dihydrochloride (compound 32), an aminoethylamino-aryl (AEAA) compound, acts as PKD-1 inhibitor. PKD-IN-1 can be used for protein kinase D (PKD)-mediated diseases research.

VU 0364439 is a mGlu4 positive allosteric modulator with an EC₅₀ of 19.8 nM. VU 0364439 modulates the GRM4/CBX4/HIF-1α signaling pathway by enhancing GRM4-CBX4 interaction. VU 0364439 can be used for the research of parkinson’s disease.

PDK1-IN-2 is a small molecule inhibitor of 3-phosphoinositol-dependent protein kinase-1 (PDK1). PDK1-IN-2 inhibits the binding of PDK1 to its substrate by competitively binding to the PIF pocket of PDK1, thereby inhibiting the kinase activity and downstream signaling of PDK1. PDK1-IN-2 can be used for cell survival and proliferation in cancer.