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
  • 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: [email protected].
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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