Potent Selective Inhibitor Research Articles

L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.

The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.

Gain-of-Function KIT Mutations Sensitize the Mutant Isoform to the Type I Tyrosine Kinase Inhibitor Crenolanib: A Rationale for the Therapeutic Use in Systemic Mastocytosis (SM) and Core Binding Factor Leukemias (CBFL)

Activating mutations of the class III receptor tyrosine kinases FLT3 and KIT are associated with certain human neoplasms, including hematologic malignancies, i.e. the majority of patients with systemic mast cell disorders (KIT) and subsets of patients with acute myelogenous leukemia (FLT3 and KIT). Crenolanib is a potent selective FLT3 inhibitor with high efficacy against internal tandem dupliction mutations (ITD) – but also secondary kinase domain mutations conferring resistance towards other TKI. Interestingly, crenolanib does not target the wildtype KIT isoform, which is believed to reduce clinical side effects such as prolonged myelosuppression observed with other TKI. Clinical studies are currently enrolling.We now show that gain-of-function mutations of KIT, including codon D816 alterations as the most prevalent mutation in SM and CBFL, sensitize the mutant isoform to crenolanib. Several mast cell and leukemia cell lines harboring autoactivating KIT or FLT3 isoforms were treated with crenolanib in dose dilution series (MOLM14, MV4;11, HMC1.1/1.2, p815). To minimize cell-type specific off-target effects, an isogenic cell model was established. The murine pro B-cell line Ba/F3 was retrovirally transduced with either a FLT3 ITD or a KIT D816 isoform. Apoptosis induction was analyzed by annexin V-based assays. FLT3/KIT tyrosine phosphorylation was assessed by western immunoblots.As previously described, the FLT3 ITD positive cell line MOLM14 revealed high sensitivity towards crenolanib with IC50s in the lowest nanomolar range. We also confirmed high sensitivity towards crenolanib ex vivo in the low nanomolar range in a native sample of a heavily pretreated patient. This patient relapsed with FLT3 ITD positive leukemia harboring a secondary D835H mutation in a subclone. Interestingly, leukemia cells in the relapse situation were much more oncogene-addicted than cells at primary diagnosis, which is in line with previous findings by others. Due to the structural homology of FLT3 D835 and KIT D816 mutations, we extended our studies to mutant-KIT mastocytosis and leukemia cell models and confirm clinically relevant antiproliferative as well as proapoptotic sensitivities towards crenolanib: for HMC mastocytosis cells harboring a KIT V560G and/or a D816V mutation, potent induction of apoptosis was observed with IC50s of 100-250nM. The murine p815 mastocytosis cell line (harboring a D814Y mutation corresponding to D816Y in humans) demonstrated a proapoptotic effect of crenolanib with an IC50 of 60 nM. Treatment of corresponding KIT or FLT3 isoform-transduced Ba/F3 cells confirmed similar IC50s in the leukemia cell lines. Parental Ba/F3cells did not show any sensitivity towards crenolanib up to concentrations of 1000 nM. Additionally, potent dephosphorylation at 100 nM of KIT D816V in Ba/F3 and HMC cells after exposure to crenolanib confirmed mutant-KIT as a target of the drug. Evaluation of a broader range of native mast cell and leukemia patient samples as well as additional leukemia cell lines and isogenic Ba/F3 KIT or FLT3 transfectants is ongoing. First results demonstrate activity of crenolanib in native cells of a subset of patient samples with SM or CBFL treated ex vivo. Even more, combination of crenolanib with anthracyclines revealed additive to superadditive proapoptotic effects. Moreover, combination of crenolanib with cladribine, a hallmark agent in the treatment of systemic mastocytosis, resulted in potent induction of apoptosis already at doses that did not display any proapoptotic effects when administered as single agents, thereby providing a rationale for combinatorial therapeutic approaches.In summary, crenolanib is effective against the KIT D816V isoform associated with several hematologic malignancies. Notably, while not as effective towards mutant-KIT compared to the FLT3 ITD isoform, the observed estimated IC50 of crenolanib is well in the range of achievable plasma concentrations and in the range of the potent KIT inhibitor dasatinib, which is successfully under clinical investigation in CBFL. Our data provide a rationale to test crenolanib as a potent inhibitor of mutant-KIT isoforms in KIT-associated neoplasms. DisclosuresSchuster:AROG Pharmaceuticals: Employment. Ramachandran:AROG: Employment.

Niemann-Pick C1-Like 1 protein: Another target for treatment of dyslipidemia? Evidence from the Myocardial Infarction Genetic Consortium and IMPROVE-IT trials.

Absorption of both dietary cholesterol and cholesterol cleared from the liver through biliary secretion contributes substantially to tight control of cholesterol homeostasis. This process is mediated by a specific transporter – Niemann-Pick C1-Like 1 (NPC1L1) protein – localized to the brush border membrane of jejunal enterocytes (Figure 1, Table 1).1 NPC1L1 was first described by Davies and colleagues in 2000 while searching for proteins homologues of human Niemann-Pick type C1 protein (NPC1) – the primary causative protein for Niemann-Pick disease type C1 – that may be involved in subcellular cholesterol trafficking.2,3 Human liver express also NPC1L1, however its physiological significance in hepatocytes remains to be elucidated. Figure 1. The Niemann–Pick C1-like-1(NPC1L1) protein (dark red) is located at the apical membrane of enterocytes and facilitates the uptake of cholesterol across the brush border membrane. In contrast, the ABCG5/G8 transporter (green) promotes the active ... Table 1 Comparison Between NPC1L1 and PCSK9 proteins. Ezetimibe – a potent selective inhibitor of NPC1L1 protein activity5 – has been shown to lower plasma levels of low density lipoprotein cholesterol (LDL-C) by 12% to 20%6–8. It was approved, in 2012, by the Food and Drug Administration (FDA) for the treatment of hypercholesterolemia on the basis of its LDL-C lowering alone, despite lack of data on its effects on clinical end-points such as death, myocardial infarction (MI), or stroke in clinical outcome studies. Ezetimibe failed to slow the progression of carotid intima-media thickness, when added to background statin therapy in patients with familial hypercholesterolemia in the landmark Ezetimibe and Simvastatin in Hypercholesterolemia Enhance Atherosclerosis Regression (ENHANCE) trial, reported in January 200811. Unfortunately these negative results cast a shadow over ezetimibe, although the ENHANCE study was heavily criticized by a significant and unexplained 18-month delay between completion of the study and publication of results. In the latest European Society of Cardiology (ESC) and American Heart Association (AHA) prevention guidelines, the use of ezetimibe alone or in combination is considered a class IIb recommendation.12,13 These results move us to more uncertainty about the benefit of this drug, and stimulated the need for conducting large genetic and clinical studies in order to test the impact of NPC1L1 inhibition on clinical outcome. Data from two large studies have been recently published and reviewed here to determine the clinical efficacy and safety of ezetimibe therapy.

Design and synthesis of highly potent and isoform selective JNK3 inhibitors: SAR studies on aminopyrazole derivatives.

The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacological properties by structure–activity relationship (SAR) studies utilizing biochemical and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metabolism and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with >80% inhibition at 10 μM. Moreover, 26n showed good solubility, good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors.

Analysis of subpocket selectivity and identification of potent selective inhibitors for matriptase and matriptase-2.

We studied the factors affecting the selectivity of peptidomimetic inhibitors of the highly homologous proteases matriptase and matriptase-2 across subpockets using docking simulations. We observed that the farther away a subpocket is located from the catalytic site, the more pronounced its role in selectivity. As a result of our exhaustive virtual screening, we biochemically validated novel potent and selective inhibitors of both enzymes.

Pharmacological characterization of the selective 11β-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes

To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11β-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11β-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585.

Design, synthesis and biological evaluation of acylhydrazone derivatives as PI3K inhibitors

Abstract Since the PI3K signaling pathway is the most commonly activated in human cancers, inhibition of PI3K is a promising approach to cancer therapy. In this study, a series of 2-methyl-5-nitrobenzeneacylhydrazones were designed and synthesized. All the new derivatives were tested by p110 α enzymatic and Rh30 cellular assays. Further enzyme selectivity profiling proved that 6e and 7 were potential selective PI3K inhibitors.

Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach.

Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.

Histone deacetylase inhibitors derived from 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine and related heterocycles selective for the HDAC6 isoform

Acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide are potent sub-type selective HDAC6 inhibitors. Constrained heterocyclic analogs based on 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine show further enhanced HDAC6 selectivity and inhibitory activity in cells. Homology models suggest that the heterocyclic spacer can more effectively access the wider catalytic channel of HDAC6 compared to other HDAC sub-types.

Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox.

Recently we constructed a homology model of the enzyme thymidylate kinase from Variola virus (VarTMPK) and proposed it as a new target to the drug design against smallpox. In the present work, we used the antivirals cidofovir and acyclovir as reference compounds to choose eleven compounds as leads to the drug design of inhibitors for VarTMPK. Docking and molecular dynamics (MD) studies of the interactions of these compounds inside VarTMPK and human TMPK (HssTMPK) suggest that they compete for the binding region of the substrate and were used to propose the structures of ten new inhibitors for VarTMPK. Further docking and MD simulations of these compounds, inside VarTMPK and HssTMPK, suggest that nine among ten are potential selective inhibitors of VarTMPK.

Abstract 5409: AZD1152-hQPA Accurins: Nanoparticle formulations showing extended release and the potential for improved therapeutic index

Abstract The prodrug, Barasertib (AZD1152) is a potent selective inhibitor of the Aurora B kinase which plays a pivotal role in chromosomal segregation during the cell cycle. In a Phase 2 randomised study in elderly AML patients unfit for intensive therapy, Barasertib showed a statistically significant improvement in Overall Complete Response Rate and a trend for improved Overall Survival as a continuous infusion over 7 days (Kantarjian et al, Cancer 2013;119:2611-2619) . The Dose Limiting Toxicities were neutropenia and stomatitis. AccurinTM nanoparticle formulations of the active metabolite, AZD1152-hQPA, have been developed utilizing medicinal nanoengineering to optimize critical nanoparticle properties such that a short infusion has the potential for extended target cover and an improved therapeutic index from increased biodistribution to the tumour site. In nude rats bearing SW620 tumours, AZD1152-hQPA Accurins gave extended target cover leading to sustained pharmacodynamic (PD) inhibition of phospho-histone H3 in the tumour relative to Barasertib at the same dose. Interestingly the Accurins gave a differentiated PD profile with maximal PD seen at later time points. This profile led to improved anti-tumour effects when AZD1152-hQPA Accurins were dosed intravenously at 25mg/kg on day 1 and 3, compared to Barasertib dosed at 25mg/kg on days 1, 2, 3, 4. Significantly, one of the AZD1152-hQPA Accurins had minimal impact on bone marrow pathology, demonstrating the potential for increased efficacy and lower toxicity at half the dose intensity of Barasertib in this preclinical model. The impact on efficacy of different dose intensities and schedules with this AZD1152-hQPA Accurin has also been explored in the equivalent nude mouse SW620 model. Together these studies demonstrate that by careful selection of formulation parameters, AZD1152-hQPA can be formulated with an extended release profile able to deliver improved efficacy and tolerability in pre-clinical models. AZD1152-hQPA Accurins offer the potential to overcome the therapeutic index challenges which previously limited the clinical development of agents in the class. Citation Format: Simon T. Barry, Elaine Cadogan, Rajesh Odedra, Susan Ashton, John Foster, Young Ho Song, Susan Low, Paula Taylor, Rebecca Ellston, Urszula Polanska, Joanne Wilson, Colin Howes, Dawn Trueman, Mike Walker, David De Witt, Marianne Ashford, Jeff Hrkach, Phil Jewsbury. AZD1152-hQPA Accurins: Nanoparticle formulations showing extended release and the potential for improved therapeutic index. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5409. doi:10.1158/1538-7445.AM2014-5409

Inhibition of Cxcr 1 and 2 Delays Preterm Delivery and Reduces Neonatal Mortality in a Mouse Model of Chorioamnionitis

Intrauterine infection is one of the main etiologies associated with preterm delivery. Cytokines involved in chorioamnionitis, including IL-1, TNF-α, IL-6, IL-8, and MCP1, activate different pathways that lead to preterm delivery. Antileukinate (AL) is a potent selective IL-8 inhibitor that binds to CXC receptors 1&2 on neutrophils, thereby inhibiting IL-8-induced neutrophil chemotaxis and degranulation. Since CXC receptors 1&2 are critically involved in the pathology of chorioamnionitis, their inhibition with AL may have therapeutic potential. Four timed-pregnant C57BL6 mice groups were studied. LPS group received LPS intraperitoneally on gestational day (GD) 15. The AL group received LPS on GD15 followed immediately by intraperitoneal AL injection and repeated on GD16, and 17. Control groups received either saline, or no injections. In the LPS group, 90% delivered within 24 hours after LPS administration compared to 20% in the AL group. The LPS group had 85% stillborn compared to 15% in the AL group. Uterine histopathology AL group showed evidence of less inflammatory reaction compared to the LPS group. Uterine tissue and serum from the AL group had a significant reduction of inflammatory cytokines compared with the LPS group. Cytokine levels in brain and lung tissues from surviving pups were not significantly different between the AL and control groups. Our data show that antileukinate significantly delays preterm delivery in a mouse model of chorioamnionitis, and reduces neonatal mortality and morbidity.

Inhibitor Binding Mode Differences Within the AGC Subfamily

Designing potent selective kinase inhibitors is an ongoing challenge due to the high level of homology within the protein kinome. The AGC family comprises ~12% of the kinome and includes many important drug targets. We compared the binding mode of two inhibitors within the catalytic domain of a set of AGC kinase family members: PKC related kinase (PRK), p90 ribosomal s6 kinase N terminal domain (RSKn), and protein kinase A (PKA). We observed that even within the closely related AGC kinase subfamily, the two ligands can bind in alternate orientations. Alternative binding modes can be attributed to specific sequence variations and structural differences, however the observation of multiple inhibitor binding modes within a subfamily highlights the difficulties in predicting the activity spectrum of kinase inhibitors. The crystal structures described herein may help in the design of potent, selective kinase inhibitors to these or related kinases.

First photoswitchable neurotransmitter transporter inhibitor: light-induced control of γ-aminobutyric acid transporter 1 (GAT1) activity in mouse brain.

Inhibition of mGAT1, the most abundant GABA transporter in the brain, enhances GABA signaling and alleviates symptoms of CNS disorders such as epilepsy assumed to be associated with low GABA levels. We have now developed a potent and subtype selective photoswitchable inhibitor of this transporter, which for the first time extends the photoswitch concept for the light-induced control of ligand affinity to active membrane transporters. The new inhibitor exhibited reduced activity upon irradiation with light, as demonstrated in GABA uptake assays and electrophysiological experiments with brain slices, and might be used as a tool compound for deepening the understanding of mGAT1 function in brain.

Substrate- and cofactor-independent inhibition of histone demethylase KDM4C.

Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging, as the active sites of KDM1A-B and KDM4A-D histone demethylases are highly conserved. Most inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide sequence or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation, and chemical modifications. Hydrogen/deuterium exchange mass spectrometry revealed that the peptide-based inhibitors target KDM4C through substrate-independent interactions located on the surface remote from the active site within less conserved regions of KDM4C. The sites discovered in this study provide a new approach of targeting KDM4C through substrate- and cofactor-independent interactions and may be further explored to develop potent selective inhibitors and biological probes for the KDM4 family.

CP-673451, a platelet-derived growth-factor receptor inhibitor, suppresses lung cancer cell proliferation and migration.

Lung cancer is the leading cause of cancer mortality in the world. Although some advances in lung cancer therapy have been made, patient survival is still poor. The platelet-derived growth factor receptors (PDGFRs) and their ligands play critical roles in the regulation of many cancer cell processes, including cell survival and cell motility. Herein, we investigate the anticancer activities of CP-673451, a potent selective inhibitor of PDGFR kinase, in non-small-cell lung cancer (NSCLC) therapy. We found that CP-673451 is effective at suppressing cell viability, inducing cell apoptosis, and inhibiting cell migration and invasion by suppressing the PDGFR downstream signaling pathway in NSCLC cells. Furthermore, CP-673451 is effective at suppressing NSCLC tumor growth in vivo. In summary, our studies suggest that CP-673451 might be a promising therapeutic compound for NSCLC.

Pyrazolylbenzyltriazoles as cyclooxygenase inhibitors: synthesis and biological evaluation as dual anti-inflammatory and antimicrobial agents

A series of pyrazolylbenzyltriazoles as celecoxib analogues having a 1,5-diaryl relationship as potential leads for the development of molecular probes for imaging of COX-2 expression was prepared by the reaction of appropriate trifluoromethyl-β-diketones (12a–12i) with 1-[(4-hydrazinophen-1-yl)methyl]-1H-1,2,4-triazole hydrochloride in refluxing ethanol. All compounds were screened for in vitro cyclooxygenase (COX) assays to determine COX-1 and COX-2 inhibitory potency. Moreover, the anti-inflammatory activity of selected compounds, which are the most selective COX-2 inhibitors in the COX inhibition assay, was investigated in vivo using a carrageenan-induced rat paw edema model. Four compounds 13b, 13e, 13g and 13h were found to be the most potent selective COX-2 inhibitors of this study with 13h showing the best COX-2 profile. Compounds 13b, 13c and 13h also showed promising anti-inflammatory (AI) activity at 5 h after the carrageenan injection that was comparable to that of the standard drug celecoxib. In addition to that, compounds were also evaluated for in vitro antimicrobial activity against two Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), two Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and two fungal strains (Saccharomyces cerevisiae and Candida albicans). Most of the compounds exhibited moderate to excellent antibacterial activity against both Gram-positive pathogens and against one Gram negative species (Escherichia coli). The selective COX-2 inhibitory activity of compound 13h is significant and it could be employed as a dual anti-inflammatory and antibacterial drug. Therefore, these compounds would represent a fruitful matrix for the development of dual anti-inflammatory antimicrobial candidates with significant COX activity.

Pharmacological identification of a guanidine-containing β-alanine analogue with low micromolar potency and selectivity for the betaine/GABA transporter 1 (BGT1).

The γ-aminobutyric acid (GABA) transporters (GATs) are key membrane transporter proteins involved in the termination of GABAergic signaling at synapses in the mammalian brain and proposed drug targets in neurological disorders such as epilepsy. To date, four different GAT subtypes have been identified: GAT1, GAT2, GAT3 and the betaine/GABA transporter 1 (BGT1). Owing to the lack of potent and subtype selective inhibitors of the non-GAT1 GABA transporters, the physiological role and therapeutic potential of these transporters remain to be fully understood. Based on bioisosteric replacement of the amino group in β-alanine or GABA, a series of compounds was generated, and their pharmacological activity assessed at human GAT subtypes. Using a cell-based [(3)H]GABA uptake assay, several selective inhibitors at human BGT1 were identified. The guanidine-containing compound 9 (2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid hydrochloride) displayed more than 250 times greater potency than the parent compound β-alanine at BGT1 and is thus the most potent inhibitor reported to date for this subtype (IC50 value of 2.5 µM). In addition, compound 9 displayed about 400, 16 and 40 times lower inhibitory potency at GAT1, GAT2 and GAT3, respectively. Compound 9 was shown to be a substrate for BGT1 and to have an overall similar pharmacological profile at the mouse orthologue. Compound 9 constitutes an interesting pharmacological tool for specifically investigating the cellular pharmacology of BGT1 and is the first small-molecule substrate identified with such a high selectivity for BGT1 over the three other GAT subtypes.

A phase 1 expansion cohort of the fibroblast growth factor receptor (FGFR) inhibitor AZD4547 in patients (pts) with advanced gastric (GC) and gastroesophageal (GOJ) cancer.

2620 Background: AZD4547 is a potent selective inhibitor of FGFR 1, 2, and 3 tyrosine kinases. Pre-clinically, gastric cancer cell lines and patient-derived xenograft models with FGFR2 gene amplifi...

Correlation of intratumoral metabolic changes measured with 18F-FDG PET parametric response maps with concentrations of CC-223, a TORC 1/2 kinase inhibitor, in human glioblastoma.

2609 Background: CC-223 is a potent selective inhibitor of mTOR kinase. Through inhibition of TORC1, TOR kinase inhibitors may result in down regulation of genes involved in glucose metabolism. A d...