Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs

  • J Med Chem. 2025 Feb 13;68(3):3591-3611. doi: 10.1021/acs.jmedchem.4c02709.
Marisa Actis  1 ,  Joel Cresser-Brown  2 ,  Elizabeth A Caine  3 ,  Martin Steger  4 ,  Anup Aggarwal  1 ,  Anand Mayasundari  1 ,  Nancy Murphy  3 ,  Gintvile Valinciute  5 ,  Yong Li  1 ,  Xiang Fu  1 ,  Lei Yang  1 ,  Graham Marsh  2 ,  Gareth Hughes  2 ,  Burhan Karadogan  2 ,  Dean Wheeler  2 ,  Mark Norley  2 ,  Freya Spain  2 ,  Marjeta Urh  3 ,  Martine F Roussel  5 ,  Björn Schwalb  4 ,  Henrik Daub  4 ,  Kristin M Riching  3 ,  Hannah Maple  2 ,  Gisele Nishiguchi  1 ,  Zoran Rankovic  1
Affiliations
  • 1. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 2. Bio-Techne (Tocris), The Watkins Building, Atlantic Road, Avonmouth, Bristol BS11 9QD, U.K.
  • 3. Promega Corporation, 2800 Woods Hollow Rd, Madison, Wisconsin 53711, United States.
  • 4. NEOsphere Biotechnologies GmbH, Fraunhoferstrasse 1, Planegg 82152, Germany.
  • 5. Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
PMID: 39813384 DOI: 10.1021/acs.jmedchem.4c02709
Abstract

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall in vitro degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor in vivo pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (8), and results of a comprehensive in vitro/vivo comparative study with analogues containing alternative CRBN-directing warheads. Our study highlights the importance of considering warhead modifications when optimizing PROTACs for oral delivery.

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