2021
DOI: 10.1021/acs.jmedchem.1c00882
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Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer

Abstract: Proteolysis targeting chimera (PROTAC) small-molecule degraders have emerged as a promising new type of therapeutic agents, but the design of PROTAC degraders with excellent oral pharmacokinetics is a major challenge. In this study, we present our strategies toward the discovery of highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics. Employing thalidomide to recruit cereblon/cullin 4A E3 ligase and through the rigidification of the linker, we discovered highly potent A… Show more

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Cited by 90 publications
(115 citation statements)
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References 61 publications
(116 reference statements)
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“…However, several orally bioavailable compounds have been developed that fall outside the rule of 5 parameters. These compounds typically have higher molecular weights and a higher number of hydrogen-bond acceptors than the rule dictates, but particular attention must also be paid to hydrogen-bond donors, topological polar surface area and cLogP 61 , as well as lipophilic efficiency 62 64 and other physicochemical parameters 65 , including those summarized in a recent review 66 . Short linkers can be used to modulate PROTAC molecular weights 67 and properties 65 , but ‘linker-ology’ does more than link the POI and E3 warheads together and influence properties.…”
Section: Outlook For the Next 20 Years Of Tpdmentioning
confidence: 99%
See 1 more Smart Citation
“…However, several orally bioavailable compounds have been developed that fall outside the rule of 5 parameters. These compounds typically have higher molecular weights and a higher number of hydrogen-bond acceptors than the rule dictates, but particular attention must also be paid to hydrogen-bond donors, topological polar surface area and cLogP 61 , as well as lipophilic efficiency 62 64 and other physicochemical parameters 65 , including those summarized in a recent review 66 . Short linkers can be used to modulate PROTAC molecular weights 67 and properties 65 , but ‘linker-ology’ does more than link the POI and E3 warheads together and influence properties.…”
Section: Outlook For the Next 20 Years Of Tpdmentioning
confidence: 99%
“…These compounds typically have higher molecular weights and a higher number of hydrogen-bond acceptors than the rule dictates, but particular attention must also be paid to hydrogen-bond donors, topological polar surface area and cLogP 61 , as well as lipophilic efficiency 62 64 and other physicochemical parameters 65 , including those summarized in a recent review 66 . Short linkers can be used to modulate PROTAC molecular weights 67 and properties 65 , but ‘linker-ology’ does more than link the POI and E3 warheads together and influence properties. The linker can contribute to the PROTAC solution conformation 68 and degradation efficiency (DC 50 /D max ) 69 , and influence the E3 ligase–POI interactions and presentation of the POI within the zone of ubiquitylation (Fig.…”
Section: Outlook For the Next 20 Years Of Tpdmentioning
confidence: 99%
“…In 2021, they used CRBN ligand to replace the VHL ligand and obtained the degrader 4 ( ARD-2128 , Fig. 4 ), 19 which achieved 67% oral bioavailability in mice. Oral administration of 4 ( ARD-2128 ) could effectively induce degradation of AR protein and effectively inhibit the growth of tumors in mice.…”
Section: Protacs Targeting Cancer-related Targetsmentioning
confidence: 99%
“…Since the publication of the initial discovery of ARD-61, the authors continued their research and have published an additional study where the PROTAC was tested specifically against enzalutamide-resistant (Enz R ) cell lines with great success compared to the inhibitor alone, resulting in an IC 50 of 472 nM against the aggressive CWR-R1 Enz R cell line and similar effects in other CRPC lines ( Kregal et al, 2020 ). After the success of their previous compounds, the Wang lab developed a CRBN-recruiting AR-PROTAC ARD-2128 ( Figure 3 ) with good oral bioavailability (67% in mice) ( Han et al, 2021 ). However, the AR antagonists-derived PROTACs will not be effective in CRPC with AR-SVs such as AR-V7 that lack the LBD.…”
Section: Protacs Targeted Towards Treatment Of Various Types Of Drug ...mentioning
confidence: 99%