2. Academic Validation
  3. Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model

Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model

  • Bioorg Med Chem Lett. 2023 Jan 15;80:129108. doi: 10.1016/j.bmcl.2022.129108.
George H Vandeveer 1,  Robert M Arduini 2,  Darren P Baker 2,  Kevin Barry 1,  Tonika Bohnert 3,  Jon K Bowden-Verhoek 4,  Patrick Conlon 1,  Patrick F Cullen 5,  Bing Guan 1,  Tracy J Jenkins 1,  Shu-Yu Liao 6,  Lin Lin 7,  Yu-Ting Liu 2,  Douglas Marcotte 6,  Elisabeth Mertsching 4,  Claire M Metrick 6,  Ella Negrou 4,  Noel Powell 1,  Daniel Scott 1,  Laura F Silvian 6,  Brian T Hopkins 8
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Cambridge, MA 02142, USA.
  • 2 Protein Science, Cambridge, MA 02142, USA.
  • 3 Drug Metabolism & Pharmacokinetics, Cambridge, MA 02142, USA.
  • 4 Immunology, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
  • 5 Bioassays & High-Throughput Screens, Cambridge, MA 02142, USA.
  • 6 Biophysics and Structural Biology, Cambridge, MA 02142, USA.
  • 7 Technical development, Cambridge, MA 02142, USA.
  • 8 Medicinal Chemistry, Cambridge, MA 02142, USA. Electronic address: Brian.Hopkins@Biogen.com.
PMID: 36538993 DOI: 10.1016/j.bmcl.2022.129108
Abstract

For the past two decades, Btk a tyrosine kinase and member of the Tec family has been a drug target of significant interest due to its potential to selectively treat various B cell-mediated diseases such as CLL, MCL, RA, and MS. Owning to the challenges encountered in identifying drug candidates exhibiting the potency block B cell activation via Btk inhibition, the pharmaceutical industry has relied on the use of covalent/irreversible inhibitors to address this unmet medical need. Herein, we describe a medicinal chemistry campaign to identify structurally diverse reversible Btk inhibitors originating from HITS identified using a fragment base screen. The leads were optimized to improve the potency and in vivo ADME properties resulting in a structurally distinct chemical series used to develop and validate a novel in vivo CD69 and CD86 PD assay in rodents.

Keywords

B cell; BTK; Fsp(3); Non-covalent inhibitor; Selectivity; X-ray.

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