2. Academic Validation
  3. Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors

Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors

  • J Med Chem. 2018 Dec 13;61(23):10665-10699. doi: 10.1021/acs.jmedchem.8b01308.
Agustin Casimiro-Garcia,  John I Trujillo 1,  Felix Vajdos 1,  Brian Juba,  Mary Ellen Banker 1,  Ann Aulabaugh 1,  Paul Balbo,  Jonathan Bauman 1,  Jill Chrencik 1,  Jotham W Coe 1,  Robert Czerwinski,  Martin Dowty 2,  John D Knafels 1,  Soojin Kwon 1,  Louis Leung 1,  Sidney Liang 1,  Ralph P Robinson 1,  Jean-Baptiste Telliez,  Ray Unwalla,  Xin Yang 1,  Atli Thorarensen
Affiliations

Affiliations

  • 1 Medicine Design , Pfizer Inc. , 445 Eastern Point Road , Groton , Connecticut 06340 , United States.
  • 2 Medicine Design , Pfizer Inc. , 1 Burtt Road , Andover , Massachusetts 01810 , United States.
PMID: 30423248 DOI: 10.1021/acs.jmedchem.8b01308
Abstract

Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.

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