Browsing Cancer Therapeutics by author "Van Montfort, Robert"
Now showing items 21-31 of 31
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Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).
Osborne, JD; Matthews, TP; McHardy, T; Proisy, N; Cheung, K-MJ; et al. (AMER CHEMICAL SOC, 2016-06-09)Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy ... -
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 ... -
Pan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody.
Tanaka, T; Thomas, J; Van Montfort, R; Miller, A; Rabbitts, T (NATURE PORTFOLIO, 2021-01-18)Intracellular antibodies are valuable tools for target validation studies for clinical situations such as cancer. Recently we have shown that antibodies can be used for drug discovery in screening for chemical compounds ... -
Privileged Structures and Polypharmacology within and between Protein Families.
Meyers, J; Chessum, NEA; Ali, S; Mok, NY; Wilding, B; et al. (AMER CHEMICAL SOC, 2018-12-13)Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 (1) and the pirin ... -
Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.
Innocenti, P; Woodward, HL; Solanki, S; Naud, S; Westwood, IM; et al. (AMER CHEMICAL SOC, 2016-04-28)Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily ... -
Structural and functional characterisation of human RNA helicase DHX8 provides insights into the mechanism of RNA-stimulated ADP release.
Felisberto-Rodrigues, C; Thomas, JC; McAndrew, C; Le Bihan, Y-V; Burke, R; et al. (PORTLAND PRESS LTD, 2019-09-13)DHX8 is a crucial DEAH-box RNA helicase involved in splicing and required for the release of mature mRNA from the spliceosome. Here, we report the biochemical characterisation of full-length human DHX8 and the catalytically ... -
Structure-based drug design: aiming for a perfect fit.
van Montfort, RLM; Workman, P (PORTLAND PRESS LTD, 2017-11-08)Knowledge of the three-dimensional structure of therapeutically relevant targets has informed drug discovery since the first protein structures were determined using X-ray crystallography in the 1950s and 1960s. In this ... -
Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1.
McGrath, S; Tortorici, M; Drouin, L; Solanki, S; Vidler, L; et al. (WILEY-V C H VERLAG GMBH, 2017-07-18)TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target, but no ... -
Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition.
Fearon, D; Westwood, IM; van Montfort, RLM; Bayliss, R; Jones, K; et al. (PERGAMON-ELSEVIER SCIENCE LTD, 2018-07-15)Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (2) and 3-amino-5-(pyridin-4-yl)pyridi ... -
Synthesis of a Ribose-Incorporating Medium Ring Scaffold via a Challenging Ring-Closing Metathesis Reaction.
Rankin, SS; Caldwell, JJ; Cronin, NB; van Montfort, RLM; Collins, I (WILEY-V C H VERLAG GMBH, 2016-09-01)A practical synthesis of a novel oxabicyclo[6.2.1]undecenetriol useful as a medicinal chemistry scaffold has been developed starting from l-ribose. The sequence involves an oxidation/Grignard addition sequence and a ... -
The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.
Couty, S; Westwood, IM; Kalusa, A; Cano, C; Travers, J; et al. (IMPACT JOURNALS LLC, 2013-08-25)The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we ...