Featured New Products 2011

Highlighted products added to the Tocris Bioscience range during 2011

December 2011

Selective casein kinase 1ε inhibitor

4281 | PF 4800567

Displays 22-fold greater potency towards CK1ε than CK1δ (IC₅₀ values are 32 and 711 nM for CK1ε and CK1δ respectively). ATP competitive. Displays minimal effect on the circadian clock.

Inhibitor of ubiquitin-specific protease (USP) 7 activity (IC₅₀ = 424 nM). Displays uncompetitive inhibition. Also inhibits USP7-mediated p53 deubiquitination (IC₅₀ = 0.8 μM). Stabilizes p53 and inhibits cancer cell growth; induces p53-dependent apoptosis in p53 wild type and null isogenic cancer cell lines.

Potent S1P₁ agonist

4289 | RP 001

EC₅₀ = 9 pM. Induces internalization and polyubiquitination of S1P₁ in vitro. Selective for S1P₁ over S1P₂ - S1P₄.

Selective activator of SK1 channels

4311 | GW 542573X

Activator of small-conductance Ca²⁺-activated K⁺ channels (SK, K_Ca2); selective for SK1 (EC₅₀ = 8.2 μM in HEK293 cells expressing hSK1) with the profile hSK1 > hSK2 = hSK3 > hIK.

November 2011

Potent and selective PLK1 inhibitor

4292 | SBE 13

IC₅₀ values are 200 pM, 875 nM and 66 μM for PLK1, PLK3 and PLK2 respectively. Targets the inactive conformation of PLK1. Displays no effect on Aurora kinase A activity. Binds and stabilizes the inactive form of PLK1. Delays cell cycle progression, reduces cell proliferation and induces apoptosis in a range of human cancer cell lines.

KCNQ2/Q3 channel opener

4305 | ICA 069673

EC₅₀ = 0.69 μM. 20-fold selective for KCNQ2/Q3 over KCNQ3/Q5 with no measurable activity over a panel of cardiac ion channels (IC₅₀ > 30 μM for hERG, Na_V1.5, L-type channels and KCNQ1). Orally active in several animal models of epilepsy.

Potent and selective inhibitor of AADACL1

4327 | JW 480

Inhibitor of the serine hydrolase enzyme KIAA1363 (AADACL1) (IC₅₀ = 20 nM in mouse brain). Impairs migration, invasion, survival and tumor growth of prostate cancer cell lines in vivo. Reduces monoalkylglycerol ether (MAGE) levels.

5-HT_2A/D₂ antagonist; atypical antipsychotic

4349 | Olanzapine

K_i values are 4 and 11 nM for 5-HT_2A and dopamine D₂ receptors respectively. Also displays affinity for a range of other receptors including D₁ and D₄, 5-HT_2C, α₁, H₁ and M_1-4 receptors (K_i values range between 1.9 and 31 nM) . Atypical antipsychotic. Displays anticholinergic properties.

Potent VEGFR-1, -2 and -3 inhibitor

4350 | Axitinib

IC₅₀ values are 0.2, 0.1 to 0.3, and 1.2 nM for VEGFR-2, VEGFR-3 and VEGFR-1 respectively. Inhibits angiogenesis and vascular permeability. Displays little activity at 'off-target' protein kinases and exhibits no significant activity in a broad protein kinase screen. Orally available.

October 2011

Selective nonpeptide NTS₁ antagonist

3721 | SR 48692

Neurotensin antagonist; selective for NTS₁ over NTS₂ (apparent affinity, K_e, is 36 nM for NTS₁). Competitively inhibits binding of [¹²⁵I]-neurotensin to HT29 and N1E115 cell membranes (IC₅₀ values are 15.3 and 20.4 nM respectively). Orally bioavailable.

Potent voltage-dependent Na_V1.8 channel blocker

4249 | A 887826

IC₅₀ = 11 nM in recombinant human Na_V1.8 channels. Reduces tactile allodynia in neuropathic rat models. 3- and 28-fold more potent at Na_V1.8 channels compared to Na_V1.2 and Na_V1.7 channels respectively.

Dual FAK/PYK2 inhibitor

4278 | PF 431396

Dual focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2) inhibitor (IC₅₀ values are 2 and 11 nM respectively). Promotes osteoblast recruitment and activity, and stimulates bone formation in ovariectomized rats.

CXCR4 antagonist

4320 | FC 131

IC₅₀ = 126 nM. Displays anti-HIV activity in assays using NL4-3 and IIIB strains (EC₅₀ = 21 nM for both strains).

MGMT inhibitor

4359 | Lomeguatrib

Inhibitor of O⁶-methylguanine-DNA methyltransferase (MGMT); (IC₅₀ = 0.009 μM in cell-free extracts from HeLa S3 cells); attenuates MGMT activity in vitro and in vivo. Enhances the antitumor activity of temozolomide (Cat. No. 2706) in both human melanoma and MCF-7 xenografts.

September 2011

Potent B-Raf inhibitor

2650 | SB 590885

K_d = 0.3 nM. Selective for B-Raf against 46 other kinases (K_{i app} values are 0.16 and 1.72 nM for B-Raf and c-Raf respectively). Decreases anchorage-independent growth of melanoma cell lines. Inhibits ERK phosphorylation and proliferation in tumor cells expressing B-Raf^V600E.

Selective RARα antagonist

3660 | BMS 195614

Neutral antagonist (K_i = 2.5 nM). Displays no significant effect on nuclear receptor corepressor (NCoR) binding; moderately decreases SMRT binding to RAR. Antagonizes agonist-induced coactivator (CoA) recruitment.

α7-selective agonist

3964 | AR-R 17779

K_i values are 190 and 16000 nM for rat α7 and α4β2 receptors respectively. CNS penetrant after systemic administration.

Potent and selective ROCK inhibitor

4009 | GSK 269962

IC₅₀ values are 1.6 and 4 nM for recombinant human ROCK1 and ROCK2 respectively. Displays greater than 30-fold selectivity for ROCK against a panel of serine/threonine kinases. Induces vasorelaxation in preconstricted rat aorta (IC₅₀ = 35 nM); lowers blood pressure in a rat model of hypertension.

Potent GPR17 agonist

4074 | PF9

Potent agonist of GPR17 (EC₅₀ = 36 pM).

August 2011

MDM2 antagonist

3984 | Nutlin-3

Inhibits the MDM2-p53 interaction (IC₅₀ = 0.09 μM) and activates p53. Antiproliferative agent; induces apoptosis in cancer cells.

γ-secretase inhibitor

4000 | MRK 560

Inhibits proteolytic cleavage of amyloid precursor protein (APP) over the Notch pathway. Reduces levels of Aβ in the brain (inhibits Aβ40 and Aβ42 in SH-SY5Y neuroblastoma cells with an IC₅₀ of 0.65 nM); attenuates plaque deposition. Orally bioavailable.

Potent and selective PLD2 inhibitor

4171 | VU 0364739

IC₅₀ = 20 nM; displays 75-fold selectivity against PLD1 (IC₅₀ = 1500 nM).

Potent ATM kinase inhibitor

4176 | KU 60019

IC₅₀ = 6.3 nM. Exhibits little to no nonspecific target effects against a panel of 229 protein kinases; displays similar target selectivity to KU 55933 (Cat. No. 3544). Inhibits migration and invasion of human glioma cells in vitro.

MCH₁ antagonist

4242 | GW 803430

IC₅₀ = 9.3 nM. Displays antiobesity and antidepressant-like effects in rats and mice. Orally active.

July 2011

Induces endoderm formation in ESCs

4015 | IDE 1

EC₅₀ = 125 nM. Thought to activate the TGF-β signaling pathway; induces Smad2 phosphorylation and increases levels of Nodal expression.

Highly selective c-Met inhibitor

4239 | PF 04217903 mesylate

High affinity; K_i = 6-7 nM against wild type c-Met. Displays >1000-fold selectivity for c-Met over a panel of 208 kinases.

Selective mTOR inhibitor

4248 | Torin 2

IC₅₀ = 2.1 nM. Displays 800-fold cellular selectivity for mTOR over PI3K (cellular EC₅₀ values are 0.25 and 200 nM for mTOR and PI3K respectively). Orally available.

Potent and selective GPR139 agonist

4255 | TC-O 9311

EC₅₀ = 39 nM in CHO-K1 cells expressing human GPR139. Displays no activity against a range of 90 diverse targets.

June 2011

RXR agonist

4064 | Fluorobexarotene

K_i = 12 nM; EC₅₀ = 43 nM at RXRα receptors. Displays similar RAR agonist activity to bexarotene; exhibits an apparent RXR binding affinity 75% greater than bexarotene.

Akt kinase inhibitor

4144 | GSK 690693

ATP-competitive pan-Akt kinase inhibitor (IC₅₀ values are 2, 13 and 9 nM for Akt1, 2 and 3 respectively). Also exhibits some inhibition for AMPK, PKA and PAK and PKC isoforms (IC₅₀ < 100 nM). Displays antiproliferative and apoptotic effects in tumor cell lines.

High affinity H₃ receptor antagonist

4020 | JNJ 5207852

pK_i values are 8.9 and 9.2 in rat and human respectively. Brain penetrant and orally active. Has 3- and 100-fold higher affinity than thioperamide (Cat. No. 0644) for rat and human H₃ receptors respectively. Suppresses slow-wave sleep; exhibits wake-promoting effects in rodent arousal models.

Potent, selective Aurora kinase A inhibitor

4066 | TC-A 2317

K_i = 1.2 nM compared to 101 nM for inhibition of Aurora kinase B. Selective over 60 other kinases (IC₅₀ values > 1000 nM). Exhibits good cell permeability and antitumor activity.

Dual specificity PPARα/γ agonist

3965 | Tesaglitazar

IC₅₀ values are 0.35 and 3.8 μM for PPARγ and PPARα respectively. Prevents atherosclerosis progression in E3L.CETP transgenic mice. Also reduces insulin resistance in obese Zucker rats. Orally active.

May 2011

Src tyrosine kinase inhibitor

3963 | AZM 475271

Reduces tumor size, vascularity and metastasis, and increases apoptosis in human pancreatic cells grown in nude mice. Also exhibits antiangiogenic activity in vitro and in vivo. Sensitizes tumor cells to the cytotoxic effects of gemcitabine (Cat. No. 3259).

Potent and selective MAGL inhibitor

3836 | JZL 184

Blocks hydrolysis of the endocannabinoid 2-arachidonyl glycerol (2-AG) in vivo in the mouse brain (IC₅₀ = 8 nM). Potentiates depolarization-induced suppression of excitability in cerebellar Purkinje neurons. Exhibits >300-fold selectivity for MAGL over FAAH in vitro.

Selective MEK inhibitor

4237 | PD 184352

K_i = 300 nM in vitro. Suppresses FGF-mediated angiogenesis in vivo and decreases VEGF expression. Enhances the therapeutic efficacy of taxol (Cat. No. 1097) in vivo. Orally active.

Potent and selective IKK-2 inhibitor

4238 | PF 184

IC₅₀ = 37 nM. Displays selectivity over 85 other kinases. Inhibits IL-1β-induced TNF-α in a steroid-insensitive in vitro model of oxidative stress.

Selective ERK5/BMK1 inhibitor

4132 | XMD 8-92

K_D values are 80, 190, 600 and 890 nM for BMK1, DCAMKL2, PLK4 and TNK1 respectively. Displays selectivity over 402 diverse kinases. Blocks growth factor-induced activation of cellular BMK1 and reduces BMK1 activity in in vitro kinase assays. Also reduces BMK1-dependent transactivating activity of MEF2C. Blocks tumor cell proliferation and tumor-associated angiogenesis.

April 2011

Non-competitive AMPA receptor antagonist

2555 | GYKI 53655

Non-competitive AMPA and kainate receptor antagonist. Analog of GYKI 52466 (Cat. No. 1454). Prolongs the survival time after MgCl₂- induced global cerebral ischemia. Exhibits anticonvulsant activity. Also blocks GluK3 homomeric receptors (IC₅₀ = 63 μM) and GluK2b(R)/GluK3 heteroreceptors (IC₅₀ = 32 μM) at high concentrations.

Potentiator of α7 nAChRs

4141 | LY 2087101

Allosteric potentiator of α7, α4β2 and α4β4 nAChRs; displays selectivity against α3β4 nAChRs. Thought to potentiate agonist-evoked α7 responses by binding within the nAChR transmembrane region.

Selective and potent COX-2 inhibitor

4206 | Valdecoxib

Selective and potent COX-2 inhibitor (in vitro IC₅₀ values are 0.005 and 140 μM for human recombinant COX-2 and COX-1 respectively). Displays potent anti-inflammatory activity in vivo.

Selective NR1/NR2A receptor antagonist

4154 | TCN 201

NMDA receptor antagonist selective for NR1/NR2A over NR1/NR2B-containing receptors (pIC₅₀ values are 6.8 and <4.3 respectively in human recombinant NR1/NR2A and NR1/NR2B FLIPR/Ca²⁺ assays).

Inhibitor of RNA helicase A (RHA)

4067 | YK 4-279

Inhibitor of RNA Helicase A (RHA) binding to the oncogenic transciption factor EWS-FLI1. Inhibits Ewing"s sarcoma family tumor (ESFT) cell growth; induces apoptosis.

March 2011

Potent cyclin-dependent kinase (cdk) 1, 2 and 9 inhibitor

3968 | AZD 5438

IC₅₀ values are 16, 6 and 20 nM respectively. Exhibits antiproliferative activity in human tumor cell lines. Blocks cell cycling at G₂-M, S and G₁ phases; reduces the proportion of actively cycling cells in vivo.

Selective NPY Y₂ antagonist

4018 | JNJ 5207787

IC₅₀ = 0.1 μM. Displays 100-fold selectivity over NPY Y₁, Y₄ and Y₅ receptors; also displays selectivity against a panel of 50 receptors, ion channels and transporters. Brain penetrant.

Selective inhibitor of MEK1/2

4192 | PD 0325901

Inhibits MEK activity in mouse colon 26 cells (IC₅₀ = 0.33 nM). Inhibits the growth of melanoma cell lines in vitro and in vivo; induces G₁-phase cell cycle arrest and apoptosis in a mouse xenograft model. Also inhibits production of proangiogenic cytokines such as VEGF. Orally active.

Selective FAAH inhibitor

4175 | PF 3845

K_i = 0.23 μM. Reduces inflammatory pain via a cannabinoid receptor-dependent mechanism. Highly efficacious and selective in vivo. Displays no activity at FAAH-2 (IC₅₀ >10 μM).

Potent and selective NK₃ antagonist

3297 | SSR 146977

K_i values are 0.26 and 19.3 nM in CHO cells expressing the human NK₃ and NK₂ receptor respectively. Also inhibits senktide (Cat. No. 1068) -induced inositol monophosphate formation and intracellular calcium mobilization (IC₅₀ = 10 nM).

February 2011

CCR5 antagonist

3756 | Maraviroc

Displays potent anti-HIV-1 activity. Prevents the interaction of HIV-1 gp120 and CCR5 (IC₅₀ = 6.4 nM), inhibiting HIV-1 entry. Also inhibits CCL3 (MIP-1α) binding to CCR5.

Potent and selective p38α inhibitor

3915 | VX 745

IC₅₀ = 10 nM. Also blocks TNFα production in LPS-stimulated HWB in vitro (IC₅₀ = 177 nM). Displays 1000-fold selectivity over closely related kinases, including ERK1, MK2 and JNK1-3.

Monopolar spindle 1 (Mps1) kinase inhibitor

3994 | AZ 3146

IC₅₀ = 35 nM. Displays selectivity over 46 other kinases including Cdk1 and aurora kinase B. Interferes with chromosome alignment and overrides spindle assembly checkpoint. Inhibits the recruitment of Mad1, Mad2 and centromere protein E (CENP-E) to kinetochores.

Selective TRPV4 antagonist

4100 | HC 067047

Reversibly inhibits currents through mouse, human and rat TRPV4 orthologs (IC₅₀ values are 17, 48 and 133 nM). Also inhibits the endogenous TRPV4-mediated response to 4α-PDH (IC₅₀ = 22 nM). Selective for TRPV4 over TRPV1, TRPV2, TRPV3 and TRPM8 channels.

Selective PPARγ agonist

4124 | Pioglitazone

EC₅₀ = 0.69 μM. Thiazolidinedione (TZD) derivative and antidiabetic agent; improves insulin sensitivity.