Design and Evaluation of a Low Hydrogen Bond Donor Count Fragment Screening Set to Aid Hit Generation of PROTACs Intended for Oral Delivery

The development of orally bioavailable PROTACs presents a significant challenge due to the inflated physicochemical properties of such heterobifunctional molecules. Molecules occupying this "beyond rule of five" space often demonstrate limited oral bioavailability due to the compounding ef...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 66; no. 11; p. 7594
Main Authors: Whitehurst, Benjamin C, Bauer, Matthias R, Edfeldt, Fredrik, Gunnarsson, Anders, Margreitter, Christian, Rawlins, Philip B, Storer, R Ian
Format: Journal Article
Language:English
Published: United States 08.06.2023
Subjects:
Administration, Oral
Biological Availability
Hydrogen Bonding
Proteins - metabolism
Proteolysis
Proteolysis Targeting Chimera
Ubiquitin-Protein Ligases - metabolism
ISSN:1520-4804, 1520-4804
Online Access:Get more information
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Summary:The development of orally bioavailable PROTACs presents a significant challenge due to the inflated physicochemical properties of such heterobifunctional molecules. Molecules occupying this "beyond rule of five" space often demonstrate limited oral bioavailability due to the compounding effects of elevated molecular weight and hydrogen bond donor count (among other properties), but it is possible to achieve sufficient oral bioavailability through physicochemical optimization. Herein, we disclose the design and evaluation of a low hydrogen bond donor count (≤1 HBD) fragment screening set to aid hit generation of PROTACs intended for an oral route of delivery. We demonstrate that application of this library can enhance fragment screens against PROTAC proteins of interest and ubiquitin ligases, yielding fragment hits containing ≤1 HBD suitable for optimizing toward orally bioavailable PROTACs.
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ISSN:1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.3c00493