Browsing ICR Divisions by author "Raynaud, Florence"
Now showing items 1-20 of 59
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2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19.
Mallinger, A; Schiemann, K; Rink, C; Sejberg, J; Honey, MA; et al. (2016-06)We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid ... -
8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.
Bavetsias, V; Lanigan, RM; Ruda, GF; Atrash, B; McLaughlin, MG; et al. (2016-02)We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a ... -
A cell-based screening method using an intracellular antibody for discovering small molecules targeting the translocation protein LMO2.
Bery, N; Bataille, CJR; Russell, A; Hayes, A; Raynaud, F; et al. (2021-04-09)Intracellular antibodies are tools that can be used directly for target validation by interfering with properties like protein-protein interactions. An alternative use of intracellular antibodies in drug discovery is ... -
A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.
Kolinsky, MP; Rescigno, P; Bianchini, D; Zafeiriou, Z; Mehra, N; et al. (2020-05)Background Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence ... -
A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202;R-Roscovitine), administered twice daily for 7-days every 21 days.
Benson, C; White, J; De Bono, JS; O'Donnell, A; Raynaud, F; et al. -
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.
Dale, T; Clarke, PA; Esdar, C; Waalboer, D; Adeniji-Popoola, O; et al. (2015-12)There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT ... -
A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity.
Kostaras, E; Kaserer, T; Lazaro, G; Heuss, SF; Hussain, A; et al. (2020-08)Background AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ... -
Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.
Bellenie, BR; Cheung, K-MJ; Varela, A; Pierrat, OA; Collie, GW; et al. (2020-04-10)Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). ... -
ALK2 inhibitors display beneficial effects in preclinical models of <i>ACVR1</i> mutant diffuse intrinsic pontine glioma.
Carvalho, D; Taylor, KR; Olaciregui, NG; Molinari, V; Clarke, M; et al. (2019-01)Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in <i>ACVR1</i>, encoding the serine/threonine kinase ALK2. Despite being an amenable ... -
Assessing histone demethylase inhibitors in cells: lessons learned.
Hatch, SB; Yapp, C; Montenegro, RC; Savitsky, P; Gamble, V; et al. (2017-01)Background Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The ... -
C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays.
Le Bihan, Y-V; Lanigan, RM; Atrash, B; McLaughlin, MG; Velupillai, S; et al. (2019-09)Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit ... -
Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy.
Faisal, A; Mak, GWY; Gurden, MD; Xavier, CPR; Anderhub, SJ; et al. (2017-04)Background The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents ... -
Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.
Hill, RM; Kuijper, S; Lindsey, JC; Petrie, K; Schwalbe, EC; et al. (2015-01)We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, ... -
Competitive SPR using an intracellular anti-LMO2 antibody identifies novel LMO2-interacting compounds.
Canning, P; Bataille, C; Bery, N; Milhas, S; Hayes, A; et al. (2021-03-29)The use of intracellular antibodies as templates to derive surrogate compounds is an important objective because intracellular antibodies can be employed initially for target validation in pre-clinical assays and subsequently ... -
Design, Synthesis and Characterization of Covalent KDM5 Inhibitors.
Vazquez-Rodriguez, S; Wright, M; Rogers, CM; Cribbs, AP; Velupillai, S; et al. (2019-01)Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major ... -
Development and validation of a LC-MS/MS method for the quantification of the checkpoint kinase 1 inhibitor SRA737 in human plasma.
Zangarini, M; Berry, P; Sludden, J; Raynaud, FI; Banerji, U; et al. (2017-07-10)Aim SRA737 is an orally active small-molecule inhibitor of checkpoint kinase 1 being investigated in an oncology setting. A HPLC-MS/MS method for quantifying plasma concentrations of SRA737 was validated.Methods & results ... -
Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in <i>KRAS</i>-Mutant Cancers.
Stewart, A; Coker, EA; Pölsterl, S; Georgiou, A; Minchom, AR; et al. (2019-08)It is increasingly appreciated that drug response to different cancers driven by the same oncogene is different and may relate to differences in rewiring of signal transduction. We aimed to study differences in dynamic ... -
Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9.
Rye, CS; Chessum, NEA; Lamont, S; Pike, KG; Faulder, P; et al. (2016-08)Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents ... -
Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.
Cheeseman, MD; Chessum, NEA; Rye, CS; Pasqua, AE; Tucker, MJ; et al. (2017-01)Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug ...