Wednesday, February 2, 2022

Selective inhibitors of JAK1 targeting a subtype-restricted allosteric cysteine

Madeline E Kavanagh, Benjamin D Horning, Roli Khattri, Nilotpal Roy, Justine P Lu, Landon R Whitby, Jaclyn C Brannon, Albert Parker, Joel M Chick, Christie L Eissler, Ashley Wong, Joe L Rodriguez, Socorro Rodiles, Kim Masuda, John R Teijaro, Gabriel M Simon, Matthew P Patricelli, Benjamin F Cravatt


The  JAK  family  of  non-receptor tyrosine  kinases  includes  four subtypes  (JAK1, JAK2, JAK3, and  TYK2)  and  is  responsible  for  signal  transduction  downstream  of  diverse  cytokine  receptors. JAK  inhibitors  have  emerged  as  important  therapies  for  immuno(onc)ological  disorders, but their use  is  limited  by  undesirable  side  effects  presumed  to  arise  from  poor  subtype  selectivity,  a common  challenge  for  inhibitors  targeting  the  ATP-binding  pocket  of  kinases.  Here,  we  describe the  chemical  proteomic  discovery  of a  druggable  allosteric  cysteine  present  in  the  non-catalytic pseudokinase  domain  of  JAK1  (C817)  and  TYK2  (C838),  but  absent  from  JAK2  or  JAK3. Electrophilic  compounds  selectively  engaging  this  site  block  JAK1-dependent transphosphorylation  and  cytokine  signaling, while  appearing  to  act largely  as  “silent”  ligands  for TYK2.  Importantly, the  allosteric  JAK1  inhibitors  do  not  impair  JAK2-dependent  cytokine signaling  and  are  inactive  in  cells  expressing  a  C817A  JAK1  mutant.  Our  findings  thus  reveal  an allosteric  approach  for  inhibiting  JAK1  with  unprecedented  subtype  selectivity. 

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure [@KayBrummond]

 Daniel P. Dempe, Chong-Lei Ji, Peng Liu, and Kay M. Brummond The Journal of Organic Chemistry, 2020 DOI: 10.1021/acs.joc.2c01530 The α-meth...