Browsing by author "Raynaud, Florence"
Now showing items 1-20 of 66
-
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. (AMER CHEMICAL SOC, 2016-06-09)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. (AMER CHEMICAL SOC, 2016-02-25)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. (AMER ASSOC ADVANCEMENT SCIENCE, 2021-04-01)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. (ELSEVIER, 2020-02-21)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 CT900, a Novel α-Folate Receptor-Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer.
Banerjee, S; Michalarea, V; Ang, JE; Ingles Garces, A; Biondo, A; et al. (AMER ASSOC CANCER RESEARCH, 2022-11-01)PURPOSE: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR-overexpressing tumors. PATIENTS AND METHODS: A 3+3 dose escalation ... -
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, J; O'Donnell, A; Raynaud, F; et al. (NATURE PUBLISHING GROUP, 2007-01-15)Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range ... -
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. (NATURE PUBLISHING GROUP, 2015-12-01)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. (SPRINGERNATURE, 2020-08-18)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. (AMER CHEMICAL SOC, 2020-04-23)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 ACVR1 mutant diffuse intrinsic pontine glioma.
Carvalho, D; Taylor, KR; Olaciregui, NG; Molinari, V; Clarke, M; et al. (NATURE PUBLISHING GROUP, 2019-05-09)Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug ... -
Assessing histone demethylase inhibitors in cells: lessons learned.
Hatch, SB; Yapp, C; Montenegro, RC; Savitsky, P; Gamble, V; et al. (BIOMED CENTRAL LTD, 2017-03-01)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 ... -
Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases.
Clarke, PA; Ortiz-Ruiz, M-J; TePoele, R; Adeniji-Popoola, O; Box, G; et al. (ELIFE SCIENCES PUBLICATIONS LTD, 2016-12-09)Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility ... -
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. (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2019-09-01)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 ... -
Capillary Microsampling of Mouse Blood in Early Pre-Clinical Studies: A Preferred Alternative to Dried Blood Spot Sampling
Roberts, J; Wilson, I; Henley, AT; Richards, M; Thai, C; et al. (OMICS Publishing Group, 2016-01-01) -
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. (NATURE PUBLISHING GROUP, 2017-04-25)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 ... -
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. (CELL PRESS, 2015-01-12)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. (ELSEVIER, 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 ... -
De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy.
Andrejeva, G; Gowan, S; Lin, G; Wong Te Fong, A-CL; Shamsaei, E; et al. (TAYLOR & FRANCIS INC, 2020-06)UNLABELLED: Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for ... -
Design, Synthesis and Characterization of Covalent KDM5 Inhibitors.
Vazquez-Rodriguez, S; Wright, M; Rogers, CM; Cribbs, AP; Velupillai, S; et al. (WILEY-V C H VERLAG GMBH, 2019-01-08)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. (FUTURE SCI LTD, 2017-07-01)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: ...