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 AR degraders with good oral pharmacokinetic properties in mice with ARD-2128 being the best compound. ARD-2128 achieves 67% oral bioavailability in mice, effectively reduces AR protein and suppresses AR-regulated genes in tumor tissues with oral administration, leading to the effective inhibition of tumor growth in mice without signs of toxicity. This study supports the development of an orally active PROTAC AR degrader for the treatment of prostate cancer and provides insights and guidance into the design of orally active PROTAC degraders.

PROTAC targeted protein degraders: the past is prologue

“…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.…”

“…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.…”

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

“…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.…”

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

“…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.…”