Download MendeleyOptimization of novel reversible Bruton's tyrosine kinase inhibitors identified using Tethering-fragment-based screens.
Hopkins, B.T., Bame, E., Bell, N., Bohnert, T., Bowden-Verhoek, J.K., Bui, M., Cancilla, M.T., Conlon, P., Cullen, P., Erlanson, D.A., Fan, J., Fuchs-Knotts, T., Hansen, S., Heumann, S., Jenkins, T.J., Marcotte, D., McDowell, B., Mertsching, E., Negrou, E., Otipoby, K.L., Poreci, U., Romanowski, M.J., Scott, D., Silvian, L., Yang, W., Zhong, M.(2019) Bioorg Med Chem 27: 2905-2913
- PubMed: 31138459
- DOI: https://doi.org/10.1016/j.bmc.2019.05.021
- Primary Citation of Related Structures:
6NZM - PubMed Abstract:
Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton's tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for the pharmaceutical industry has been the identification of reversible, selective, potent molecules for inhibition of BTK. Herein, we report application of Tethering-fragment-based screens to identify low molecular weight fragments which were further optimized to improve on-target potency and ADME properties leading to the discovery of reversible, selective, potent BTK inhibitors suitable for pre-clinical proof-of-concept studies.
Organizational Affiliation:
Biogen Inc., 225 Binney Street, Cambridge, MA 02142, United States. Electronic address: Brian.Hopkins@biogen.com.
