Screening of a new class of Janus kinase 3 inhibitors targeted at its non‐kinase domain

Abstract

BackgroundJanus kinase 3 is a non‐receptor tyrosine kinase protein and abnormal activation of this protein is associated with several metabolic and immunological complications including autoimmune disorders, hypersensitive reactions and in certain cases leukemia. The existing Jak3 inhibitors have been found to be non‐specific and interact with Jak members and further have a black box warning on its label by FDA. Therefore, there is a pressing need to design a new class of specific inhibitors for Jak3 with immunosuppressive and anti‐leukemic properties. Previously we reported that non‐kinase domain in particular regulate the kinase activity of the protein. Further, we extensively reviewed the important structural role of FERM and SH2 domain in the functioning of Jak3 protein. In this report, we explored and validated potential Jak3 inhibitors targeted to FERM and Sh2 domains of Jak3.MethodologyThe FERM and Sh2 domains were modelled using the Phyre2 server and validated by constructing the Ramachandran plot. The model quality was also checked and validated using Procheck and Discovery Studios. We adopted a high‐thoroughput Insilco parallel screening of potential Jak3 inhibitors from the ZINC database using Dockblaster software.ResultsFollowing compounds are found to bind to the FERM domain Barbituric acid derivative, Dextromoramide, Estazolam, Zaleplon and Dioxaphetyl butyrate were binding with highest affinity to FERM domain whereas N‐methylsulfonylmethanesulfonamide, N‐(2‐cyanoethyl)‐N‐methyl‐propane‐1‐sulfonamide,N‐(1‐cyano‐1‐methyl‐ethyl)‐2‐methoxyethanesulfonamide, 5‐methyl‐2‐propylsulfonyl‐benzamide,N‐[(2‐cyanophenyl)methyl]‐N‐ethylmethanesulfonamide, 2R)‐1‐propylsulfonylpiperidine‐2‐carboxamide were binding to the SH2 domain. The FERM and SH2 domain together displayed the highest binding affinity to (2S,3S)‐3‐amino‐2‐hydroxy‐pentanedioic, 5‐[(2R)‐3‐hydroxy‐2‐(methylamino)‐3‐oxo‐propyl]‐1‐methylpyrazole‐4‐carboxylic, (3R)‐3‐amino‐3‐(1H‐imidazo[4,5‐b]pyridin‐2‐yl)propanoic, (2R,3R)‐3‐amino‐2‐hydroxy‐pentanedioic, 5‐[(2R)‐2‐amino‐3‐hydroxy‐3‐oxo‐propyl]‐1‐methyl‐pyrazole‐4‐carboxylic. It is noteworthy that the protein folding of Jak3 full length protein reduces its binding affinity to its inhibitors as the inhibitors for FERM and SH2 domain bind with higher affinity to the domain itself. We are further designing inhibitors specific to the interface between FERM and Sh2 domain. and found (2S,3S)‐3‐amino‐2‐hydroxy‐pentanedioic binds with highest affinity to the linker between FERM and Sh2 domain. BiConclusionCollectively, we have identified promising Jak3 inhibitors having less cross inhibition of other essential kinases. Equally important, results from these studies are expected to have a positive translational impact by providing previously unknown options for the treatment of a wide variety of diseases including CRC, RA, and T1D where Jak3 activation is essential for the disease progression.Support or Funding InformationThis work was supported by National Institutes of Health Grants DK081661 (to N. K.) and GM109528 (to N. K. and J. M.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.