4.7 Article

Discovery of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors

Journal

BIOORGANIC CHEMISTRY
Volume 126, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105860

Keywords

Noncovalent BTK inhibitor; B cell malignancy; Autoimmune disorder; Tyrosine kinase inhibitor; Scaffold hopping

Funding

  1. National Key Research and Development Program [2016YFA0502304]
  2. National Natural Science Foundation of China [81825020]
  3. Na-tional Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
  4. Fundamental Research Funds for the Central Universities
  5. National Program for Special Supports of Eminent Professionals
  6. National Program for Support of Top-Notch Young Professionals

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This study developed selective non-covalent BTK inhibitors by scaffold hopping and found that compound 2 and 4 exhibited high BTK inhibition potency. These compounds showed great ability to inhibit tumor growth in cell and animal models.
Bruton's tyrosine kinase (BTK) is a promising target in the treatment of B cell malignancies and autoimmune disorders. Developing selective non-covalent BTK inhibitors is an important strategy to overcome the side effects and drug resistance induced by covalent BTK inhibitors. In this article, we designed and synthesized pyrrolo [1,2-a] quinoxalin-4(5H)-one and imidazo [1,2-a] quinoxalin-4(5H)-one based selective noncovalent BTK inhibitors via scaffold hopping from BMS-986142 and investigated their biological activities. Among the synthesized compounds, pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives 2 and 4 showed great BTK inhibition potency with IC50 value at 7.41 nM and 11.4 nM, respectively. Besides, they showed equivalent or even better potency in U937 and Ramos cells than BMS-986142. The kinase selectivity profiling study illustrated the excellent selectivity of compound 2 against a panel of 468 kinases. In U937 xenograft models, compound 2 could significantly inhibit tumor growth with TGI = 65.61%. In all, we provided a new scaffold as non-covalent selective BTK inhibitors and the representative compounds exhibited potency both in vitro and in vivo.

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