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Published on: December 7, 2014
Optimization of novel reversible Bruton's tyrosine kinase inhibitors identified using Tethering-fragment-based
Brian T Hopkins1, Eris Bame1, Noah Bell2
1Biogen Inc., 225 Binney Street, Cambridge, MA 02142, United States.
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.
Insights
Researchers developed new reversible, selective, and potent Bruton
Area of Science:
- Medicinal Chemistry and Drug Discovery
- Oncology
- Pharmacology
Background:
- Ibrutinib, a covalent Bruton's tyrosine kinase (BTK) inhibitor, was approved in 2012 for B-cell malignancies.
- Numerous clinical trials have explored covalent BTK inhibitors for cancer treatment.
- Developing reversible, selective, and potent BTK inhibitors remains a significant challenge.
Purpose of the Study:
- To identify novel reversible, selective, and potent inhibitors of Bruton's tyrosine kinase (BTK).
- To optimize low molecular weight fragments for improved on-target potency and ADME properties.
- To discover compounds suitable for pre-clinical proof-of-concept studies in oncology.
Main Methods:
- Application of Tethering-fragment-based screening (TFS) to identify initial low molecular weight fragments.
- Iterative optimization of identified fragments to enhance potency and pharmacokinetic properties.
- Evaluation of optimized compounds for selectivity and suitability for pre-clinical studies.
Main Results:
- Successfully identified low molecular weight fragments using TFS.
- Optimized fragments demonstrated improved on-target potency and ADME properties.
- Discovered reversible, selective, and potent BTK inhibitors.
Conclusions:
- Tethering-fragment-based screening is an effective strategy for discovering novel BTK inhibitors.
- The identified inhibitors are potent, selective, and reversible, suitable for pre-clinical development.
- This work addresses the need for improved BTK-targeted therapies in oncology.
