Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model

The lack of selective and safe in vivo IRE1α tool
molecules
has limited the evaluation of IRE1α as a viable target to treat
multiple myeloma. Focus on improving the physicochemical properties
of a literature compound by decreasing lipophilicity, molecular weight,
and basicity allowed the discovery of a novel series with a favorable
in vitro safety profile and good oral exposure. These efforts culminated
in the identification of a potent and selective in vivo tool compound, G-5758, that was well tolerated following multiday oral administration
of doses up to 500 mg/kg. G-5758 demonstrated comparable
pharmacodynamic effects to induced IRE1 knockdown as measured by XBP1s
levels in a multiple myeloma model (KMS-11).