Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs

Rohan Kalyan Rej; Srinivasa Rao Allu; Joyeeta Roy; Ranjan Kumar Acharyya; I. N. Chaithanya Kiran; Yesu Addepalli; V. Dhamodharan

doi:10.3390/ph17040494

Pharmaceuticals (Apr 2024)

Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs

Rohan Kalyan Rej,
Srinivasa Rao Allu,
Joyeeta Roy,
Ranjan Kumar Acharyya,
I. N. Chaithanya Kiran,
Yesu Addepalli,
V. Dhamodharan

Affiliations

Rohan Kalyan Rej: Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Srinivasa Rao Allu: Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Joyeeta Roy: Rogel Cancer Center, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Ranjan Kumar Acharyya: Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
I. N. Chaithanya Kiran: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02139, USA
Yesu Addepalli: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
V. Dhamodharan: Institute of Organic Chemistry, Center for Nanosystems Chemistry, University of Wuerzburg, Am Hubland, 97074 Würzburg, Germany

DOI: https://doi.org/10.3390/ph17040494
Journal volume & issue: Vol. 17, no. 4
p. 494

Abstract

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Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality that show promise to open a target space not accessible to conventional small molecules via a degradation-based mechanism. PROTAC degraders, due to their bifunctional nature, which is categorized as ‘beyond the Rule of Five’, have gained attention as a distinctive therapeutic approach for oral administration in clinical settings. However, the development of PROTACs with adequate oral bioavailability remains a significant hurdle, largely due to their large size and less than ideal physical and chemical properties. This review encapsulates the latest advancements in orally delivered PROTACs that have entered clinical evaluation as well as developments highlighted in recent scholarly articles. The insights and methodologies elaborated upon in this review could be instrumental in supporting the discovery and refinement of novel PROTAC degraders aimed at the treatment of various human cancers.

Published in Pharmaceuticals

ISSN: 1424-8247 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Pharmacy and materia medica
Website: http://www.mdpi.com/journal/pharmaceuticals/

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Abstract

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