Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model PMID: 38748820

ADC Targets in Oncology

2026-04-10

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

J Med Chem. 2024 Jun 13;67(11):8708-8729. doi: 10.1021/acs.jmedchem.3c02425.

Marie-Gabrielle Braun ¹ , Avi Ashkenazi ¹ , Ramsay E Beveridge ² , Georgette Castanedo ¹ , Heidi Ackerly Wallweber ¹ , Maureen H Beresini ¹ , Kevin R Clark ¹ , Tom De Bruyn ¹ , Liqiang Fu ³ , Paul Gibbons ¹ , Fan Jiang ⁴ , Susan Kaufman ¹ , David Kan ¹ , James R Kiefer ¹ , Jean-Philippe Leclerc ² , Alexandre Lemire ² , Cuong Ly ¹ , Ehud Segal ¹ , Jessica Sims ¹ , Weiru Wang ¹ , Wentao Wei ⁴ , Liang Zhao ² , Jacob B Schwarz ¹ , Joachim Rudolph ¹

Affiliations

Abstract

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).