2. Academic Validation
  3. Phenyl Dihydrouracil: An Alternative Cereblon Binder for PROTAC Design

Phenyl Dihydrouracil: An Alternative Cereblon Binder for PROTAC Design

  • ACS Med Chem Lett. 2023 Jan 4;14(2):141-145. doi: 10.1021/acsmedchemlett.2c00436.
Jamie A Jarusiewicz 1,  Satoshi Yoshimura 2,  Anand Mayasundari 1,  Marisa Actis 1,  Anup Aggarwal 1,  Kevin McGowan 1,  Lei Yang 1,  Yong Li 1,  Xiang Fu 1,  Vibhor Mishra 3,  Richard Heath 3,  Shilpa Narina 4,  Shondra M Pruett-Miller 4,  Gisele Nishiguchi 1,  Jun J Yang 2,  Zoran Rankovic 1
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 2 Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 3 Protein Production Facility, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 4 Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
PMID: 36793425 DOI: 10.1021/acsmedchemlett.2c00436
Abstract

Thalidomide and its analogues are frequently used in PROTAC design. However, they are known to be inherently unstable, undergoing hydrolysis even in commonly utilized Cell Culture media. We recently reported that phenyl glutarimide (PG)-based PROTACs displayed improved chemical stability and, consequently, improved protein degradation efficacy and cellular potency. Our optimization efforts, aiming to further improve the chemical stability and eliminate the racemization-prone chiral center in PG, led us to the development of phenyl dihydrouracil (PD)-based PROTACs. Here we describe the design and synthesis of LCK-directing PD-PROTACs and compare their physicochemical and pharmacological properties to those of the corresponding IMiD and PG analogues.

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