Featured New Products 2012

Highlighted products added to the Tocris Bioscience range during 2012

December 2012

Potent and selective S1P₁ receptor antagonist

3602 | W146

K_i = 18 nM. Displays no effect at S1P₂, S1P₃ or S1P₅. Enhances capillary leakage and restores lymphocyte egress in vivo.

Highly potent and selective NR2B antagonist

K_i = 0.8 nM. Blocks NR2B-mediated calcium influx in Ltk cells (K_i = 9.7 nM). Selective for NR2B subunit over α₁-adrenergic receptors and hERG channels (IC₅₀ values are 730 nM and 2900 nM respectively). Displays efficacy in the rat carrageenan-induced mechanical hyperalgesia assay.

Potent LRRK2 inhibitor

4534 | CZC 54252

IC₅₀ values are 1.28 nM and 1.85 nM for wild-type and G2019S mutant forms of LRRK2 respectively. Attenuates neuronal injury induced by LRRK2-G2019S mutant activity in primary human neurons (EC₅₀ = 1 nM).

Pan protein kinase D inhibitor; cell permeable

4644 | CID 2011756

IC₅₀ values are 0.6, 0.7 and 3.2 μM for PKD2, PKD3 and PKD1 respectively. Cell permeable (EC₅₀ = 10 μM for PKD1 inhibition). ATP-competitive.

Potent and selective α₁β₁ inhibitor

4664 | Obtustatin

IC₅₀ = 0.8 nM for α₁β₁ binding to type IV collagen. Selective for α₁β₁ over α₂β₁, α_IIbβ₃, α_vβ₃, α₄β₁, α₅β₆, α₁β₁, α₉β₁ and α₄β₇. Inhibits FGF2-stimulated angiogenesis in the chicken chorioallantoic model. Displays antitumor efficacy in a synergistic mouse model of Lewis lung carcinoma; blocks human melanoma growth in nude mice.

November 2012

Biotinylated anandamide analog

4104 | MM-22

Acts as a probe for visualizing the accumulation and intracellular trafficking of anandamide. Blocks anandamide uptake (IC₅₀ = 0.5 μM in HaCaT cells); prevents interaction with FAAH, CB₁ and TRPV1.

Selective α7 nAChR agonist

4477 | A 844606

EC₅₀ values are 1.4 and 2.2 μM at human and rat receptors respectively. Displays no measurable effect on α4β2 nAChRs. Stimulates α7 nAChR-induced ERK1/2 phosphorylation in PC12 cells.

Selective allosteric activator of Lyn kinase

4582 | MLR 1023

EC₅₀ = 63 nM; displays no significant activity against a range of 47 other kinases, including other Src family kinases such as Fyn, Lck and Src kinase. Reduces blood glucose levels without affecting in vivo insulin secretion. Orally bioavailable.

Hepatocyte nuclear factor 4α antagonist

4641 | BI 6015

Represses expression of known HNF4α target genes. Decreases HNF4α DNA binding. Exhibits cytotoxic activity in a range of tumor cell lines, including human hepatocellular carcinoma.

BET bromodomain inhibitor

4650 | I-BET 151

Blocks recruitment of BET to chromatin. Induces apoptosis and G₀/G₁ cell cycle arrest in MLL-fusion leukemic cell lines in vitro (IC₅₀ values are 15, 26, 120 and 192 nM for NOMO1, MV4;11, MOLM13 and RS4;11 cell lines respectively); reduces BCL2 expression in NOMO1 cells. Improves survival in two rodents models of MLL-fusion leukemia in vivo.

October 2012

Dual ERK1/RasGAP inhibitor

4433 | Pluripotin

Maintains embryonic stem cell (ESC) self-renewal. Enables propagation of undifferentiated murine ESCs in the absence of leukemia inhibitor factor (LIF).

Smoothened (Smo) antagonist

4585 | MRT 10

IC₅₀ = 0.5 μM in HEK293 cells transiently expressing mouse Smo. Inhibits ShhN-induced Gli luciferase reporter activity in Shh-light2 cells (IC₅₀ = 2.5 μM); acts as an inverse agonist during nontranscriptional hedgehog pathway activation (IC₅₀ = 2.5 μM in HEK293 cells).

Histone demethylase JMJD3/UTX inhibitor

4594 | GSK J4

Blocks demethylation of histone H3K27. Attenuates lipopolysaccharide (LPS)-induced proinflammatory cytokine production in primary human macrophages (IC₅₀ = 9 μM for the inhibition of TNFα release). Cell permeable, ethyl ester derivative of GSK J1 (Cat. No. 4593).

Potent TrkB agonist

4607 | LM 22A4

IC₅₀ = 47 nM. Induces activation of Trk, Akt and ERK in mouse hippocampus and striatum. Reverses deficits in motor task learning in mice following traumatic brain injury; restores respiratory function in a rat model of Rett syndrome.

Potent Hsp90 inhibitor

4608 | BIIB 021

K_i = 1.7 nM. Displays no significant activity at a range of ATP-binding kinases or Na⁺K⁺ ATPase. Induces degradation of HER-2 in vitro (EC₅₀ = 38 nM in MCF-7 cells). Inhibits growth and promotes cell death in a variety of human tumor cells. Orally bioavailable.

September 2012

Selective PAR₁ antagonist

2614 | RWJ 56110

Displays no activity at PAR₂, PAR₃, or PAR₄ subtypes. Blocks thrombin-induced platelet aggregation and activation of MAPK in HUVECs. Also inhibits angiogenesis in a chick embryo angiogenesis model in vivo.

Highly selective GSK-3 inhibitor

4423 | CHIR 99021

IC₅₀ values are 6.7 and 10 nM for GSK-3β and GSK-3α respectively. Exhibits >500-fold selectivity for GSK-3 over closely related kinases; also displays >800-fold selectivity against 45 additional enzymes and receptors.

BET bromodomain inhibitor

4445 | PFI 1

Exhibits inhibitory activity at bromodomain-containing protein (BRD) 2 and BRD4.

Tankyrase inhibitor

4514 | JW 55

Inhibitor of the PARP domain of tankyrase 1 and 2 (TNKS1/2). Activity results in stabilization of Axin2 and increased degradation of β-catenin; inhibits the β-catenin signaling pathway. Also shown to decrease canonical Wnt signaling in SW480 and HCT-15 colon carcinoma cell lines; reduces cell cycle progression and proliferation in SW480 cells in vitro.

Potent and selective CGRP receptor antagonist

4561 | BIBN 4096

IC₅₀ values are 0.03 and 6.4 nM for human and rat CGRP receptors respectively. Displays high affinity for human CGRP receptors (K_i = 14.4 pM); exhibits no significant affinity for 75 other receptors.

August 2012

Positive allosteric modulator of M₅ receptors

4404 | VU 0365114

EC₅₀ values are 2.7 μM for human M₅, and >30 μM for M₁, M₂, M₃ and M₄ receptors.

Fluorescent mitochondrial H₂O₂ indicator

4428 | MitoPY1

Fluorescent probe for imaging hydrogen peroxide (H₂O₂) in mitochondria of living cells. Displays enhanced emission at 528 nm in the presence of H₂O₂. Selective for H₂O₂ over superoxide, nitric oxide and hydroxyl radical. Detects local increases in H₂O₂ in an in vitro model of Parkinson's Disease.

Negative allosteric modulator at mGlu₅

4438 | MFZ 10-7

K_i = 0.67 nM. Potently inhibits mGlu₅ glutamate-mediated calcium mobilization (IC₅₀ = 1.22 nM).

Potently induces chondrogenesis in MSCs

4513 | Kartogenin

Potently induces differentiation of human mesenchymal stem cells (MSCs) into chondrocytes (EC₅₀ = 100 nM). Reduces disease severity in a mouse model of osteoarthritis; displays protective effects against osteoarthritic stimuli in mature chondrocytes in vitro.

KCNQ2 and KCNQ4 channel opener

4519 | ML 213

EC₅₀ values are 230 and 510 nM for KCNQ2 and KCNQ4 respectively. Displays >80-fold selectivity against KCNQ1, KCNQ3 and KCNQ5 in a thallium-based fluorescence assay.

July 2012

Highly potent P2Y₁₂ receptor antagonist

3983 | PSB 0739

K_i = 24.9 nM. Unlike clopidogrel (Cat. No. 2490), does not require bioactivation.

Negative allosteric modulator at mGlu₅

4438 | MFZ 10-7

K_i = 0.67 nM. Potently inhibits mGlu₅ glutamate-mediated calcium mobilization (IC₅₀ = 1.22 nM).

CaM kinase III (eEF-2 kinase) inhibitor

4483 | A 484954

IC₅₀ = 0.28 μM in enzymatic assay. Reduces eEF-2 phosphorylation with little effect on cancer cell growth.

GLUT1 inhibitor

4484 | STF 31

Inhibits glucose uptake in renal cell carcinoma (RCC) 4 cells. Activity causes necrotic cell death in von Hippel-Lindau (VHL)-deficient RCC cells.

USP7 inhibitor

4485 | P 22077

EC₅₀ = 8.6 μM; also inhibits the closely related deubiquitinase (DUB) USP47. Demonstrates downstream inhibition of HDM2 and claspin in vitro. Inhibits USP7-mediated p53 deubiquitination.

June 2012

Potent and selective P2Y₆ agonist

4260 | MRS 2957 triethylammonium salt

EC₅₀ = 12 nM. Displays 14- and 66-fold selectivity against P2Y₂ and P2Y₄ receptors respectively.

Potent and selective NOD1 inhibitor

4354 | ML 130

Displays 36-fold selectivity for NOD1 over NOD2 (IC₅₀ values are 0.56 and >20 μM for NOD1 and NOD2 respectively). Inhibits NOD1-induced NF-κB activation in HEK293 cells with no cytotoxicity. Shown to alter subcellular targeting of NOD1; also thought to alter the conformation of NOD1 protein in vitro.

Allosteric Bcr-abl tyrosine kinase inhibitor

4399 | GNF 2

IC₅₀ = 267 nM; inhibits proliferation and induces apoptosis in Bcr-abl-expressing cells. Selective for Bcr-abl over a panel of serine, threonine and tyrosine kinases. Non-ATP-competitive.

Highly potent, selective GSK-3 inhibitor

4431 | A 1070722

K_i = 0.6 nM for GSK-3α and GSK-3β. Displays high selectivity (> 50-fold) for GSK-3 over a panel of other kinases tested, including CDK family members. Decreases phosphorylation of microtubule-associated protein Tau in vitro; protects rat primary cortical neurons against β amyloid and glutamate challenge. Brain penetrant.

Potent, selective HIF1α PHD2 inhibitor

4451 | IOX 2

Displays over 100-fold selectivity for PHD2 over factor inhibiting HIF-1 (FIH-1) and histone demethylases KDM4A, KDM4C, KDM4E and KDM6B. Cell permeable.

May 2012

Potent C5a receptor antagonist

3333 | NDT 9513727

IC₅₀ = 11.6 nM; selective for human C5aR (IC₅₀ for rat and mouse C5aR > 10 μM). Exhibits inverse agonist pharmacokinetics. Blocks degranulation response in C5a-stimulated U937 cells (IC₅₀ = 7.1 nM). Orally bioavailable.

Potent, reversible and selective FAAH inhibitor

4355 | TC-F 2

IC₅₀ values are 28 and 100 nM for human and rat FAAH respectively. Noncovalent inhibitor; displays selectivity for FAAH over cannabinoid-related targets (IC₅₀ > 20 μM for CB₁, CB₂ and TRPV1). Active in vivo.

Potent S1P₁ receptor agonist

4363 | TC-SP 14

EC₅₀ values are 0.042 and 3.47 μM for human S1P₁ and S1P₃ respectively. Attenuates immune response to antigen challenge and reduces circulating blood lymphocyte counts in a rodent model of delayed-type hypersensitivity. Orally bioavailable.

Selective Na_V1.7 blocker

4435 | TC-N 1752

IC₅₀ values are 0.17, 0.3, 0.4 and 1.1 μM at hNa_V1.7, hNa_V1.3, hNa_V1.4 and hNa_V1.5 respectively. Also inhibits tetrodotoxin-sensitive sodium channels. Displays analgesic efficacy in the formalin pain model.

Potent and selective P2X₇ antagonist

4473 | A 804598

IC₅₀ values are 8.9 nM, 9.9 nM and 10.9 nM for mouse, rat and human P2X₇ receptors respectively. Selective for P2X₇ receptors (IC₅₀ > 5-10 μM for a wide array of cell surface receptors and ion channels assayed). Binds with high affinity (K_{i app} = 2.4 nM for rat P2X₇ receptors).

April 2012

Highly potent, selective PDK1 inhibitor

4143 | GSK 2334470

IC₅₀ ~ 10 nM. Exhibits no effect on other kinases including Aurora, ROCK, p38 MAPK and PI3K. Suppresses T-loop phosphorylation and subsequent activation of PDK1 substrates S6K1, SGK and RSK in HEK293, U87 and mouse embryonic fibroblast cell lines.

Potent MK-2 inhibitor

4279 | PF 3644022

Potent, ATP-competitive inhibitor of mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK-2) (IC₅₀ = 5.2 nM; K_i = 3 nM). Inhibits TNFα production in U937 monocytic cells and PBMCs (IC₅₀ = 160 nM); exhibits oral efficacy in acute and chronic inflammatory models.

sGC activator; induces G₁ cell cycle arrest

4307 | YC 1

Significantly elevates cGMP levels and inhibits collagen-stimulated aggregation of washed rabbit platelets ; induces relaxation in denuded phenylephrine-contracted rabbit aortic rings (EC₅₀ = 1.9 μM). Also induces G₁ cell cycle arrest in two HCC cell lines.

Selective G9a and GLP HMTase inhibitor

4343 | UNC 0638

IC₅₀ values are < 15 nM and 19 nM for G9a and GLP respectively, and > 10000 nM for a range of other histone lysine methyltransferases. Potently inhibits dimethylation of H3K9 in MCF-7 cells (IC₅₀ = 70 nM). Cell permeable.

Potent EphB4 kinase inhibitor

4405 | NVP BHG 712

Selective inhibitor of EphB4 kinase; exhibits selectivity for EphB4 over more than 40 other kinases in vitro, including FGFR3. Inhibits EphB4 autophosphorylation in transiently transfected HEK 293 cells. Also inhibits VEGF-induced angiogenesis in vivo.

March 2012

Selective inhibitor of TGF-βRI

3264 | GW 788388

IC₅₀ values are 0.018 and 0.093 μM for ALK5 binding and for TGF-β cellular assay respectively. Inhibits esopheageal squamous cell carcinoma (ESCC)-induced neoangiogenesis. Orally active.

Potent and selective TRPV1 antagonist

4319 | A 784168

IC₅₀ = 25 nM for inhibition of TRPV1 activation by 50 nM capsaicin. Displays no activity against a range of receptors, including TRPA1, GABA, opioid, and purinergic receptors.

ASK1 inhibitor

4429 | NQDI 1

Selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1, MAP3K5) (IC₅₀ = 3 μM, K_i = 500 nM).

KLF5 inhibitor

4446 | CID 5951923

Inhibitor of Krüppel-like factor 5 (KLF5) transcription factor (IC₅₀ = 2.3 μM). Selective for colon cancer cells in a panel of 60 different cancer cell lines.

Potent B-Raf inhibitor

4453 | GDC 0879

IC₅₀ = 0.13 nM against purified B-Raf^V600E. Activity reduces phospho-ERK (pERK) levels (IC₅₀ = 63 nM in the Malme-3M cell line). Inhibits the Raf/MEK/ERK signaling pathway in V600E B-Raf mutant cell lines. Does not activate apoptotic pathways in A375 or Colo205 cell lines. Orally bioavailable.

February 2012

Selective D₃ antagonist

4207 | SB 277011A

pK_i values are 8.0, 6.0, 5.0 and <5.2 for D₃, D₂, 5-HT_1D and 5-HT_1B respectively. Brain penetrant.

Specific E3 ubiquitin ligase inhibitor

4375 | SMER 3

Specific inhibitor of a yeast SCF family E3 ubiquitin ligase (SCF^Met30) in vitro and in vivo. Induces the expression of MET genes; blocks cell proliferation. Enhancer of Rapamycin (Cat. No. 1292).

Potent and selective DAPK1 inhibitor

4301 | TC-DAPK 6

ATP-competitive inhibitor of death-associated protein kinase 1 (DAPK1) (IC₅₀ values are 69 and 225 nM for DAPK1 and DAPK3 respectively, when assayed with 10 μM ATP). Displays selectivity for DAPK1 over a range of 48 other kinases, including Abl, AMPK, Chk1, Met and Src (IC₅₀ > 10 μM).

mGlu₅ antagonist

4394 | VU 0360223

Potent antagonist of mGlu₅ (IC₅₀ = 61 nM). Displays no activity at mGlu_1-4 and mGlu_7-8.

N-WASP inhibitor

4434 | Wiskostatin

Inhibitor of neural Wiskott-Aldrich syndrome protein (N-WASP) activity. Interacts with the regulatory GTPase-binding domain of N-WASP; inhibits activation of Arp2/3 complex by maintaining N-WASP in an inactive conformation. Also inhibits PIP₂-induced actin polymerization (EC₅₀ ~ 4μM).