Hi-JAK-ing the ubiquitin system : the design and physicochemical optimisation of JAK PROTACs

Shah, Rishi R. and Redmond, Joanna M. and Mihut, Andrei and Menon, Malini and Evans, John P. and Murphy, John A. and Bartholomew, Michelle A. and Coe, Diane M. (2020) Hi-JAK-ing the ubiquitin system : the design and physicochemical optimisation of JAK PROTACs. Bioorganic and Medicinal Chemistry, 28 (5). 115326. ISSN 0968-0896

[thumbnail of Shah-etal-BMC-2020-the-design-and-physicochemical-optimisation-of-JAK-PROTACs]
Preview
Text. Filename: Shah_etal_BMC_2020_the_design_and_physicochemical_optimisation_of_JAK_PROTACs.pdf
Accepted Author Manuscript
License: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 logo

Download (820kB)| Preview

    Abstract

    PROTACs have recently emerged as a novel paradigm in drug discovery.They can hijack existing biological machinery to selectively degrade proteins o finterest, in a catalytic fashion. Here we describe the design, optimisation and biological activity of a set of novel PROTACs targeting the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) of proximal membrane-bound proteins.The JAK family proteins display membrane localisation by virtue of their association with cytoplasmic tails of cytokine receptors, and there are no reports of a successful PROTAC strategy being deployed against this class of proteins. JAK PROTACs from two distinct JAK chemotypes were designed, optimising the physicochemical properties for each template to enhance cell permeation. These PROTACs are capable of inducing JAK1 and JAK2 degradation, demonstrating an extension of the PROTAC methodology to an unprecedented class of protein targets. A number of known ligase binders were explored, and it was found that PROTACs bearing an inhibitor of apoptosis protein (IAP) ligand induced significantly more JAK degradation over VonHippel–Lindau (VHL) and Cereblon (CRBN. In addition, the mechanism of action of the JAK PROTACs was elucidated, and it was confirmed that JAKdegradation was both IAP-and proteasome-dependent.