Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer

Abstract

We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

“…The negative control compound 26 (Table 2) exhibits a reversed stereochemistry at C-4 of the hydroxyproline unit, a modication which abolishes binding to VHL. 42,43 For the composition of compound 27, the same PEG4 linker as in 24 was installed, but a methylated derivative of VH032, which possesses an enhanced binding affinity for VHL 43 was used.…”

“…Despite the extraordinary importance of VHL in the PROTAC eld, this E3 ligase has not yet been utilized for the successful development of CDK4/6 PROTACs and was even considered to be inappropriate. 37 We followed a combinatorial approach towards VHL-based PROTACs by assembling four different linkers of various lengths and lipophilicities and two VHL ligands bearing different exit vectors for linker connection, 43,61,62 which were ultimately incorporated into the nal palbociclib-derived CDK4/6d. Noteworthy, all PROTACs of the rst, 'amide' subseries (Tables 2 and S6, ESI †) had pronounced ability to suppress CDK4/6 protein levels.…”

“…24 whose linker corresponded to that of 8, for further chemical modication (Table S6, ESI †). The tailored introduction of a methyl group in the VHL-addressing part, 43 resulted in the optimized PROTAC 27 (Table 2) with respect to both, potency and selectivity. Extensive experiments with 27 addressed the concentration-and time-dependent depletion and the conrmation of the VHL ligase/proteasome-mediated protein degradation ( Fig.…”

“…The activity of 29, when compared with its close relative 30 was unexpected, also in the light of the same lipophilicity of both compounds (Table 2). In the subsequent optimization step, inspired by previous reports, 43,45,61,63 the valine-isoindolinone moiety of 29 was replaced by tert-leucine acylated with a cyanocyclopropanecarbonyl (33) or uorocyclopropanecarbonyl group (34). These two structural modications led to CDK4/6d with outstanding properties, combining strong degrading potency with remarkable CDK6 selectivity, as evidenced by their selectivity indices of 46 and 31, respectively.…”

Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling

“…Moreover, AKT has been reported to have kinase-independent functions (Vivanco et al, 2014) that would reduce efficacy of small molecule inhibitors, and resistance to AKT inhibitors can arise in some contexts due to upregulation of AKT3 (Stottrup et al, 2016). Degraders have been reported to abrogate kinase-independent functions (Cromm et al, 2018) and overcome inhibitor-induced compensatory upregulation of target proteins (Cai et al, 2012;Han et al, 2019). Targeted AKT degradation may be a promising alternative approach for therapeutic intervention in cancers with PI3K/AKT pathway alterations.…”