Microwave-assisted synthesis of pomalidomide building blocks for rapid PROTAC and molecular glue development
Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation via S N Ar on 4-fluorothalidomide. Here, we optimize a microwave-assisted synthesis (MAS) of pomalidomide building blocks, achieving...
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| Published in | Chemical communications (Cambridge, England) Vol. 61; no. 24; pp. 467 - 4673 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Royal Society of Chemistry
19.03.2025
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| Abstract | Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation
via
S
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Ar on 4-fluorothalidomide. Here, we optimize a microwave-assisted synthesis (MAS) of pomalidomide building blocks, achieving high yields within 15 min - boosting yield by at least 14% at gram scale without the need for purification. Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method's utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs.
A rapid and efficient microwave-assisted synthesis of pomalidomide analogs, improving upon prior methods to accelerate the discovery and optimization of degraders like clinical candidate ARV-110. |
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| AbstractList | Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation via SNAr on 4-fluorothalidomide. Here, we optimize a microwave-assisted synthesis (MAS) of pomalidomide building blocks, achieving high yields within 15 min - boosting yield by at least 14% at gram scale without the need for purification. Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method’s utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs. Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation via SNAr on 4-fluorothalidomide. Here, we optimize a microwave-assisted synthesis (MAS) of pomalidomide building blocks, achieving high yields within 15 min - boosting yield by at least 14% at gram scale without the need for purification. Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method's utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs.Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation via SNAr on 4-fluorothalidomide. Here, we optimize a microwave-assisted synthesis (MAS) of pomalidomide building blocks, achieving high yields within 15 min - boosting yield by at least 14% at gram scale without the need for purification. Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method's utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs. Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation via S N Ar on 4-fluorothalidomide. Here, we optimize a microwave-assisted synthesis (MAS) of pomalidomide building blocks, achieving high yields within 15 min - boosting yield by at least 14% at gram scale without the need for purification. Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method’s utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs. Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation S Ar on 4-fluorothalidomide. Here, we optimize a microwave-assisted synthesis (MAS) of pomalidomide building blocks, achieving high yields within 15 min - boosting yield by at least 14% at gram scale without the need for purification. Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method's utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs. Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation via S N Ar on 4-fluorothalidomide. Here, we optimize a microwave-assisted synthesis (MAS) of pomalidomide building blocks, achieving high yields within 15 min - boosting yield by at least 14% at gram scale without the need for purification. Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method's utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs. A rapid and efficient microwave-assisted synthesis of pomalidomide analogs, improving upon prior methods to accelerate the discovery and optimization of degraders like clinical candidate ARV-110. |
| Author | Israelian, Johan Saqib, Bilal Gunning, Patrick T Keillor, Jeffrey W Wright, Timothy B de Araujo, Elvin D Abdallah, Diaaeldin I Hasan, Lina S Patel, Naman H |
| AuthorAffiliation | Department of Chemistry Department of Chemical & Physical Sciences University of Toronto Mississauga School of Molecular Biosciences, University of Glasgow, Glasgow Department of Chemistry and Biomolecular Sciences University of Ottawa University of Toronto |
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| Author_xml | – sequence: 1 givenname: Diaaeldin I surname: Abdallah fullname: Abdallah, Diaaeldin I – sequence: 2 givenname: Johan surname: Israelian fullname: Israelian, Johan – sequence: 3 givenname: Lina S surname: Hasan fullname: Hasan, Lina S – sequence: 4 givenname: Naman H surname: Patel fullname: Patel, Naman H – sequence: 5 givenname: Jeffrey W surname: Keillor fullname: Keillor, Jeffrey W – sequence: 6 givenname: Timothy B surname: Wright fullname: Wright, Timothy B – sequence: 7 givenname: Bilal surname: Saqib fullname: Saqib, Bilal – sequence: 8 givenname: Elvin D surname: de Araujo fullname: de Araujo, Elvin D – sequence: 9 givenname: Patrick T surname: Gunning fullname: Gunning, Patrick T |
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| Title | Microwave-assisted synthesis of pomalidomide building blocks for rapid PROTAC and molecular glue development |
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