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

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

Affiliations

  • 1 Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Paraza Pharma Inc., 2525 Ave. Marie-Curie, Montreal, QC, Canada H4S 2E1.
  • 3 WuXi AppTec Co., Ltd., Shanghai 200131, P. R. China.
  • 4 VIVA Biotech, No. 735, Ziping Road, Pudong New Area, Shanghai 201321, China.
PMID: 38748820 DOI: 10.1021/acs.jmedchem.3c02425
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).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161672
    98.91%, IRE1α Inhibitor