Hudson, L., Mui, J., Vázquez, S., Carvalho, D.M., Williams, E., Jones, C., Bullock, A.N. & Hoelder, S.
(2018). Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure–Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept. Journal of medicinal chemistry,
Woodward, H.L., Innocenti, P., Cheung, K.-., Hayes, A., Roberts, J., Henley, A.T., Faisal, A., Mak, G.W., Box, G., Westwood, I.M., et al.
(2018). Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4 H-1,2,4-triazol-3-yl)phenyl)-6-methyl- N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine (BOS172722). J med chem,
Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4- d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4- d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate..
McGrath, S., Tortorici, M., Drouin, L., Solanki, S., Vidler, L., Westwood, I., Gimeson, P., Van Montfort, R. & Hoelder, S.
(2017). Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1. Chemistry - a european journal,
Innocenti, P., Woodward, H.L., Solanki, S., Naud, S., Westwood, I.M., Cronin, N., Hayes, A., Roberts, J., Henley, A.T., Baker, R., et al.
(2016). Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. J med chem,
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 on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model..
Drouin, L., McGrath, S., Vidler, L.R., Chaikuad, A., Monteiro, O., Tallant, C., Philpott, M., Rogers, C., Fedorov, O., Liu, M., et al.
(2015). Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B. J med chem,
The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 (BAZ2-ICR) of the BAZ2A/B bromodomains through rapid optimization of a weakly potent starting point. A key feature of the presented inhibitors is an intramolecular aromatic stacking interaction that efficiently occupies the shallow bromodomain pockets. 13 represents an excellent chemical probe for functional studies of the BAZ2 bromodomains in vitro and in vivo. .
Gurden, M.D., Westwood, I.M., Faisal, A., Naud, S., Cheung, K.-., McAndrew, C., Wood, A., Schmitt, J., Boxall, K., Mak, G., et al.
(2015). Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance. Cancer research,
Innocenti, P., Woodward, H., O'Fee, L. & Hoelder, S.
(2015). Expanding the scope of fused pyrimidines as kinase inhibitor scaffolds: synthesis and modification of pyrido[3,4-d]pyrimidines. Org biomol chem,
Fused pyrimidine cores are privileged kinase scaffolds, yet few examples of the 2-amino-pyrido[3,4-d]pyrimidine chemotype have been disclosed in the context of kinase inhibitor programs. Furthermore, no general synthetic route has been reported to access 2-amino-pyrido[3,4-d]pyrimidine derivatives. Here we report a versatile and efficient chemical approach to this class of molecules. Our strategy involves the concise preparation of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine intermediates and their efficient derivatisation to give novel compounds with potential as kinase inhibitors. .
Innocenti, P., Cheung, K.-., Solanki, S., Mas-Droux, C., Rowan, F., Yeoh, S., Boxall, K., Westlake, M., Pickard, L., Hardy, T., et al.
(2012). Design of potent and selective hybrid inhibitors of the mitotic kinase Nek2: structure-activity relationship, structural biology, and cellular activity. J med chem,
We report herein a series of Nek2 inhibitors based on an aminopyridine scaffold. These compounds have been designed by combining key elements of two previously discovered chemical series. Structure based design led to aminopyridine (R)-21, a potent and selective inhibitor able to modulate Nek2 activity in cells..
Vidler, L.R., Brown, N., Knapp, S. & Hoelder, S.
(2012). Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites. J med chem,
Bromodomains are readers of the epigenetic code that specifically bind acetyl-lysine containing recognition sites on proteins. Recently the BET family of bromodomains has been demonstrated to be druggable through the discovery of potent inhibitors, sparking an interest in protein-protein interaction inhibitors that directly target gene transcription. Here, we assess the druggability of diverse members of the bromodomain family using SiteMap and show that there are significant differences in predicted druggability. Furthermore, we trace these differences in druggability back to unique amino acid signatures in the bromodomain acetyl-lysine binding sites. These signatures were then used to generate a new classification of the bromodomain family, visualized as a classification tree. This represents the first analysis of this type for the bromodomain family and can prove useful in the discovery of inhibitors, particularly for anticipating screening hit rates, identifying inhibitors that can be explored for lead hopping approaches, and selecting proteins for selectivity screening..
Watts, E., Heidenreich, D., Tucker, E., Raab, M., Strebhardt, K., Chesler, L., Knapp, S., Bellenie, B. & Hoelder, S.
Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity. Journal of medicinal chemistry,