posted on 2021-04-21, 16:44authored byMalcolm
P. Huestis, Matthew R. Durk, Charles Eigenbrot, Paul Gibbons, Thomas L. Hunsaker, Hank La, Dennis H. Leung, Wendy Liu, Shiva Malek, Mark Merchant, John G. Moffat, Christine S. Muli, Christine J. Orr, Brendan T. Parr, Frances Shanahan, Christopher J. Sneeringer, Weiru Wang, Ivana Yen, Jianping Yin, Joachim Rudolph, Michael Siu
Structure-based optimization of a
set of aryl urea RAF inhibitors
has led to the identification of Type II pan-RAF inhibitor GNE-9815
(7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal
polar hinge contacts, the pyridopyridazinone hinge binder moiety affords
exquisite kinase selectivity in a lipophilic efficient manner. The
improved physicochemical properties of GNE-9815 provided a path for
oral dosing without enabling formulations. In vivo evaluation of GNE-9815 in combination with the MEK inhibitor cobimetinib
demonstrated synergistic MAPK pathway modulation in an HCT116 xenograft
mouse model. To the best of our knowledge, GNE-9815 is among the most
highly kinase-selective RAF inhibitors reported to date.