Chemicals & Small Molecules

Ceramides are bioactive sphingolipids which induce apoptosis in cells. Ceramidases (CDase) which hydrolyze the fatty acid chain keep ceramide levels in check and have been proposed as a target for small-molecule inhibitors for anti-cancer therapy. Ceranib-2 inhibits cellular CDase activity with an IC50 = 28 uM in SKOV3 cells and does not show significant cytotoxity up to 100uM. Incubations of SKOV3 cells with Ceranib-2 resulted in an increase in all ceramide species and a dose-dependant decrease in sphingosine and S1P. Ceranib-2 suppressed tumor growth in a mouse model with subcutaneous JC cell tumors.References1) J.M Draper et al. "Discovery and Evaluation of Inhibitors of Human Ceramidase" Mol. Cancer Ther. 2011 10 2052-20612) H.S. Vethakanraj et al. "Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines" Biophys. Biochem. Res. Commun. 2015 464 833-839.

Benzo[a]pyrene (BaP 3 4-Benzopyrene 3 4-Benzpyrene Benzo[def]chrysene) is a procarcinogenic polyaromatic hydrocarbon (PAH) found in coal tar and other byproducts from the combustion of organic material. It is metabolized by cytochrome P450 1A1 (CYP1A1) to benzo[a]pyrene-7 8-dihydrodiol-9 10-epoxide which is carcinogenic. This metabolite intercalates DNA thus disrupting DNA copying and inducing mutations. Benzo[a]pyrene is used as a chemical carcinogen in cancer models.

CYM50308 is a potent and selective S1P4 receptor agonist with EC50 of 37.7 nM - 79.1nM. It is inactive against the S1P1 S1P2 and S1P3 receptors up to 25 μM and the S1P5 receptor up to 2.1 μM.References1) Urbano et al. Discovery synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z 5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2- (alkylimino)thiazolidin-4-one chemotype Bioorganic & Medicinal Chemistry Letters 2011 6739-6745.2) Guerrero et al. Identification of a novel agonist of the sphingosine 1-phosphate receptor 4 (S1P4) Probe Reports from the NIH Molecular Libraries Program. http://www.ncbi.nlm.nih.gov/books/NBK143556/

LPA is a growth factor-like mediator and a ligand for multiple GPCR. The LPA2 GPCR mediates antiapoptotic and mucosal barrier-protective effectes in the gut. LPA GPCR activate antiapoptotic kinase pathways inhibit aopotosis promote cell regeneration and augment DNA repair. GRI977143 can be used for the attenuation of programmed cell death elicited by radiation and chemotherapeutic agents and also shows strong radioprotective action by rescuing cells from apoptosis and mice irradiated with lethal doses of γ-irradiation.

FPA-124 is a cell-permeable inhibitor of Akt (IC50 = 100 nM) binding to the PH and kinase domains. It inhibits cell proliferation in Colo357 BxPC3 BT20 and PC3 cancer cell lines with IC50 values ranging from 7-55 nM. FPA-124 inhibited tumor growth in mice with negligible toxicity.References Powered by Bioz See more details on Bioz1) V. Barve et al. "Synthesis Molecular Characterization and Biological Activity of Novel SyntheticDerivatives of Chromen-4-one in Human Cancer Cells" J. Med. Chem. 2006 49 3800-3808.2) Biscetti F. G. Straface et al. (2009). "Pioglitazone enhances collateral blood flow in ischemic hindlimb of diabetic mice through an Akt-dependent VEGF-mediated mechanism regardless of PPARgamma stimulation." Cardiovasc Diabetol 8: 49.3) Brito P. M. R. l. Devillard et al. (2009). "Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in smooth muscle cells." Atherosclerosis 205(1): 126.

KP372-1 directly inhibits the kinase activities of Akt PDK1 and Flt3 (Fms-like tyrosine kinase 3) which are aberrantly activated in acute myelogenous leukemia (AML). It is a cell permeant inhibitor that decreases the colony-forming ability of AML cells (IC50 < 200 nM) with minimal cytoxic effects on normal hematopoietic progenitor cells. KP372-1 has also been shown to suppress cell proliferation and induce apoptosis in thyroid cancer cells and gliobastoma. Provided as a 1:1 mixture of regioisomers.References Powered by Bioz See more details on Bioz1) M. Mandal et al. "The Akt Inhibitor KP372-1 Suppresses Akt Activity and Cell Proliferation and Induces Apoptosis in Thyroid Cancer Cells" Br. J. Cancer 2005 92 1899-1905.2) Z. Zeng et al "Simultaneous Inhibition of PDK1/AKT and Fms-Like Tyrosine Kinase 3 Signaling by a Small-Molecule KP372-1 Induces Mitochondrial Dysfunction and Apoptosis in Acute Myelogenous Leukemia." Cancer Res. 2006 66 3737-3746.

Wortmannin is a specific irreversible inhibitor of phosphatidylinositol 3-kinases (IC50 ~ 2-3 nM). It shows similar potency for all classes of PI3Ks.Publications Powered by Bioz See more details on Bioz1. Takahashi K Tanaka T Suzuki K. Directional control of WAVE2 membrane targeting by EB1 and phosphatidylinositol 3 4 5-triphosphate. Cell Signal. 2010;22(3):510-8.

LY294002 is a selective cell permeable potent and specific inhibitor of phosphatidylinositol 3-kinase (IC50 = 1.4 μM; purified PI 3-kinase). It does not significantly inhibit PKC PKA MAP kinase S6 kinase EGFrK c-src kinase PI 4-kinase DAG kinase or rabbit kidney ATPase at concentrations of 50 μM. Induces apoptosis. In intact neutrophils stimulated with fMet-Leu-Phe LY294002 completely abolished PI 3-kinase activity at 50 μM without cell toxicity.Publications Powered by Bioz See more details on Bioz1. Coronas-Serna JM Fernández-Acero T Molina M Cid VJ. A humanized yeast-based toolkit for monitoring phosphatidylinositol 3-kinase activity at both single cell and population levels. Microbial Cell. 2018;5(12):545-54.2. Chang P Walker MC Williams RS. Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid. Neurobiol Dis. 2014;62:296-306.3. Fernández-Acero T RodrÃguez-Escudero I Vicente F Monteiro MCn Tormo JR Cantiza

5-quinoxilin-6-methylene-1 3-thiazolidine-2 4-dione (AS605240) is an ATP-competitive inhibitor of PI3-Kγ (IC50 = 8 nM). It is selective for the γ-isoform (IC50: PI 3-Kα = 60 nM PI 3-Kβ = 270 nM PI 3-Kδ = 300 nM) and shows no notable activity against a wide array of protein kinases at 1 μM. In addition AS605240 suppresses the progression of joint inflammation in a mouse model of rheumatoid arthritis and suppresses inflammation in a mouse model of lupus.References Powered by Bioz See more details on Bioz1) M. Camps et al. "Blockade of PI3Kg suppresses joint inflammation and damage in mouse models of rheumatoid arthritis" Nature Medicine 2005 11 936-943.2) D.F. Barber et al. "PI3Kg inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus" Nature Medicine 2005 11 933-935.