Browsing by author "Rossanese, Olivia"
Now showing items 1-12 of 12
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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). ... -
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 ... -
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 ... -
Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.
Pierrat, OA; Liu, M; Collie, GW; Shetty, K; Rodrigues, MJ; et al. (NATURE PORTFOLIO, 2022-11-03)By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. ... -
Discovery of a potent stapled helix peptide that binds to the 70N domain of replication protein A.
Frank, AO; Vangamudi, B; Feldkamp, MD; Souza-Fagundes, EM; Luzwick, JW; et al. (AMER CHEMICAL SOC, 2014-03-27)Stapled helix peptides can serve as useful tools for inhibiting protein-protein interactions but can be difficult to optimize for affinity. Here we describe the discovery and optimization of a stapled helix peptide that ... -
Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.
Abbott, JR; Patel, PA; Howes, JE; Akan, DT; Kennedy, JP; et al. (AMER CHEMICAL SOC, 2018-09-13)Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant ... -
DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer.
Kanu, N; Cerone, MA; Goh, G; Zalmas, L-P; Bartkova, J; et al. (BMC, 2016-09-15)BACKGROUND: The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Although many studies have documented the downstream effects of APOBEC3 activity through next-generation sequencing, ... -
Encoding BRAF inhibitor functions in protein degraders.
Miller, DSJ; Voell, SA; Sosič, I; Proj, M; Rossanese, OW; et al. (ROYAL SOC CHEMISTRY, 2022-06-22)Various BRAF kinase inhibitors were developed to treat cancers carrying the BRAFV600E mutation. First-generation BRAF inhibitors could lead to paradoxical activation of the MAPK pathway, limiting their clinical usefulness. ... -
Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo.
Huckvale, R; Harnden, AC; Cheung, K-MJ; Pierrat, OA; Talbot, R; et al. (AMER CHEMICAL SOC, 2022-06-23)The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 ... -
Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.
Lloyd, MG; Huckvale, R; Cheung, K-MJ; Rodrigues, MJ; Collie, GW; et al. (AMER CHEMICAL SOC, 2021-12-09)We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors ... -
Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.
Davis, OA; Cheung, K-MJ; Brennan, A; Lloyd, MG; Rodrigues, MJ; et al. (AMER CHEMICAL SOC, 2022-06-23)To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on ... -
Role for the Histone Demethylase KDM4B in Rhabdomyosarcoma via CDK6 and CCNA2: Compensation by KDM4A and Apoptotic Response of Targeting Both KDM4B and KDM4A.
Walters, ZS; Aladowicz, E; Villarejo-Balcells, B; Nugent, G; Selfe, JL; et al. (MDPI, 2021-04-06)Histone demethylases are epigenetic modulators that play key roles in regulating gene expression related to many critical cellular functions and are emerging as promising therapeutic targets in a number of tumor types. We ...